Peroxisome proliferator activated receptor modulators

ABSTRACT

The present invention is directed to compounds represented by the following structural formula, and pharmaceutically acceptable salts thereof, Formula I. (Formula I); wherein: (a) R5 is selected from the group consisting of (C 1 –C 6 )alkyl, (C 1 –C 6 )alkenyl, aryl (C 0 –C 4 )alkyl, aryloxy(C 0 –C 4 )alkyl, arylthio(C 0 –C 4 )alkyl, and further wherein when R5 is alkyl, R5 can optionally combine with W to form a 6 membered cycloheteroalkyl ring that is fused with the oxazole or thiazole ring to which the R5 group is attached; (b) R9 is selected from the group consisting of C 1 –C 5 alkyl, C 1 –C 5 alkenyl, and arylC 0 –C 3 alkyl. (c) T 1  is selected from the group consisting of C and N, (d) W is selected from the group consisting of CH 2 , C(O)N(R21), N(R21), N(R21)CH 2 , O, OCH 2 , S, and SO 2 ; and (e) X is selected from the group consisting of C, CH 2 C, and CCH 2

This Application claims the benefit of U.S. Provisional Application Ser.No. 60/359,808, filed Feb. 25, 2002, and PCT Application Ser. No.PCT/US03/02679, filed Feb. 13, 2003.

BACKGROUND OF THE INVENTION

Peroxisome Proliferator Activated Receptors (PPARs) are members of thenuclear hormone receptor super family, which are ligand-activatedtranscription factors regulating gene expression. Various subtypes ofPPARs have been discovered. These include PPARα, NUC1, PPARγ and PPARδ.

The PPARα receptor subtypes are reported to be activated by medium andlong-chain fatty acids. They are involved in stimulating beta-oxidationof fatty acids and with the activity of fibrates reportedly producing asubstantial reduction in plasma triglycerides and moderate reduction inlow density lipoprotein (LDL) cholesterol. PPARα, PPARγ and PPARδreceptors have been implicated in diabetes mellitus, cardiovasculardisease, obesity, Syndrome X and gastrointestinal disease, such as,inflammatory bowel disease. Syndrome X is the combination of symptomsincluding hyperinsulemia combined with hypertension, elevated bodyweight, elevated triglycerides and elevated LDL.

Current PPAR agonist treatment for Syndrome X relates to the use ofthiazolidinediones (TZDs) or other insulin sensitivity enhancers (ISEs).TZDs are a class of PPAR gamma agonists which have been shown toincrease the sensitivity of insulin sensitive cells. Increasing insulinsensitivity rather than the amount of insulin in the blood reduces thelikelihood of hypoglycemic coma. However, TZDs and ISEs typically havelittle effect in preventing the cardiovascular part of Syndrome X inthat their administration usually dose not result in the lowering oftriglycerides and LDL-cholesterol while raising HDL-cholesterol.Furthermore, side effects commonly associated with treatment with TZDscan include significant weight gain, and, for troglitazone, can includeliver toxicity. Therefore, a need exists for new pharmaceutical agentswhich affect treat or prevent cardiovascular disease, particularly thatassociated with Syndrome X, while preventing or minimizing weight gain,and more preferably while improving insulin sensitivity. It may beespecially desirable when the active pharmaceutical agent selectivelymodulates a PPAR receptor subtype to provide an especially desirablepharmacological profile.

SUMMARY OF THE INVENTION

The present invention is directed to compounds represented by thefollowing structural Formula I:

and pharmaceutically acceptable salts thereof, wherein:

-   -   (a) R3 and R4 are each independently selected from the group        consisting of hydrogen, (C₁–C₄)alkyl, halo, and (C₁–C₆)alkoxy;    -   (b) R30 and R40 are each independently selected form the group        consisting of hydrogen, (C₁–C₄)alkyl, and (C₁–C₆)alkoxy;    -   (c) R5 is selected from the group consisting of (C₁–C₆)alkyl,        (C₁–C₆)alkenyl, aryl(C₀–C₄)alkyl, aryloxy(C₀–C₄)alkyl,        arylthio(C₀–C₄)alkyl, wherein said aryl(C₀–C₄)alkyl,        aryloxy(C₀–C₄)alkyl, and arylthio(C₁–C₄)alkyl are each        independently optionally substituted with from one to three        substituents each independently selected from R5′, and further        wherein when R5 is alkyl, R5 can optionally combine with W to        form a 6 membered cycloheteroalkyl ring that is fused with the        oxazole or thiazole ring to which the R5 group is attached;    -   (d) R5′ are each independently selected from the group        consisting of halo, —(O)—(C₁–C₅)alkylCOOH, C₁–C₅alkyl,        C₁–C₅alkylCOOH, and CF₃;    -   (e) R6 is selected from the group consisting of trihalomethyl,        trihalomethoxy, hydroxy(C₀–C₃)alkyl, (C₁–C₄)alkyl,        (C₁–C₆)alkylNC(O)—, tetramethyldioxaborolanyl, halo,        —C(O)(C₁–C₄)alkyl, —O—(C₁–C₂)alkyl-CO₂H, aryloxy, arylthio,        —C(O)N(C₁–C₆)alkyl, (C₁–C₄)alkoxy, tetrahydropyranyloxy,        morpholinyl, (C₅–C₆)cycloalkyloxy, (C₅–C₆)heterocyclo-oxy,        pyridinyl, pyrimidinyl, pyrazinyl and aryl(C₀–C₄)alkyl, wherein        said pyridinyl, pyrimidinyl, pyrazinyl, aryl(C₀–C₄)alkyl,        aryloxy, (C₅–C₆)heterocyclo-oxy, and arylthio are each        optionally substituted with from one to three substituents        independently selected from R6′;    -   (f) R6′ and R9′ are each independently selected from the group        consisting of CF₃, C₁–C₄ alkyl, halo, hydroxy(C₁–C₃)alkyl,        C₁–C₃alkoxy, and —C(O)CH₃;    -   (g) R7 and R8 are each independently selected from the group        consisting of hydrogen, CF₃, and (C₁–C₄) alkyl;    -   (h) R9 is selected from the group consisting of C₁–C₅alkyl,        C₁–C₅alkenyl, and arylC₀–C₃alkyl, wherein said arylalkyl is        optionally substituted with from one to three substituents each        independently selected from R9′;    -   (i) R10 is selected from the group consisting of hydrogen, and        C1–C₅alkyl;    -   (j) Q is selected from the group consisting of O, a single bond,        and C;    -   (k) T₁ is selected from the group consisting of C and N;    -   (l) W is selected from the group consisting of CH₂, C(O)N(R21),        N(R21), N(R21)CH₂, O, OCH₂, S, and SO₂;    -   (m) R21 is selected from the group consisting of hydrogen and        C₁–C₂alkyl;    -   (n) X is selected from the group consisting of C, CH₂C, and        CCH₂;    -   (O) Y and Z are each independently selected from the group        consisting of O, N and S, wherein at least one of Y and Z is        selected from the group consisting of O and S;    -   (p) A is an functional group selected from the group consisting        of carboxyl, C₁–C₃alkylnitrile, carboxamide, and (CH₂)_(n)        COOR19;    -   (q) n is 0, 1, 2 or 3; and    -   (r) R19 is selected from the group consisting of hydrogen, and        C₁–C₃alkyl.

Another embodiment of the present invention is a compound of Formula I′:

and pharmaceutically acceptable salts thereof, wherein:

-   -   (a) R3 and R4 are each independently selected from the group        consisting of hydrogen, (C₁–C₄)alkyl, halo, and (C₁–C₆)alkoxy;    -   (b) R5 is selected from the group consisting of (C₁–C₆)alkyl,        (C₁–C₆)alkenyl, substituted aryl(C₀–C₄)alkyl, substituted        aryloxy(C₁–C₄)alkyl, substituted arylthio(C₀–C₄)alkyl,        unsubstituted aryl(C₀–C₄)alkyl, unsubstituted        aryloxy(C₀–C₄)alkyl, and unsubstituted arylthio(C₀–C₄)alkyl;    -   (c) R6 is selected from the group consisting of trihalomethyl,        halo, hydroxy, hydroxy(C₁–C₃)alkyl, (C₁–C₄)alkyl, —C(O)        (C₂–C₄)alkyl, —C(O)N(C₁–C₆)alkyl, —O—(C₁–C₂)alkyl-CO₂H,        (C₁–C₄)alkyloxy, (C₅–C₆) cycloalkyloxy, (C₅–C₆)heterocyclic,        (C₅–C₆)heterocyclo-oxy, substituted (C₅–C₆)heterocyclo-oxy,        aryl(C₀–C₄)alkyl, substituted aryl(C₀–C₄)alkyl;    -   (d) R7 and R8 are each independently selected from the group        consisting of hydrogen, CF₃, and (C₁–C₄)alkyl;    -   (e) R9 is selected from the group consisting of C1–C₅alkenyl,        unsubtituted arylC₀–C₃alkyl, subtituted arylC₀–C₃alkyl,        substituted arylthioC₁–C₂alkyl, unsubstituted        arylthioC₁–C₂alkyl, substituted aryloxyC₁–C₂alkyl, unsubstituted        aryloxyC₁–C₂alkyl and C1–C₅alkyl;    -   (f) R10 is hydrogen or methyl;    -   (g) Q is selected from the group consisting of O and C;    -   (h) W is selected from the group consisting of O, S, and SO₂;    -   (i) X is selected from the group consisting of CH, CH₂CH, and        CHCH₂;    -   (j) Y and Z are each independently selected from the group        consisting of O, N and S;    -   (k) A is an functional group selected from the group consisting        of carboxyl, C₁–C₃alkylnitrile, carboxamide, and (CH₂)_(n)        COOR19;    -   (l) n is 0, 1, 2 or 3; and    -   (m) R19 is selected from the group consisting of hydrogen,        optionally substituted C1–C4alkyl and optionally substituted        arylmethyl.

In one embodiment, the present invention also relates to pharmaceuticalcompositions which comprising at least one compound of the presentinvention, or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier.

In another embodiment, the present invention relates to a method ofselectively modulating a PPAR delta receptor by contacting the receptorwith at least one compound represented by Structural Formula I, andpharmaceutically acceptable salts thereof.

In another embodiment, the present invention relates to a method ofmodulating one or more of the PPAR alpha, beta, gamma, and/or deltareceptors.

In a further embodiment, the present invention relates to a method ofmaking a compound represented by Structural Formula I.

The compounds of the present invention are believed to be effective intreating and preventing Syndrome X, Type II diabetes, hyperglycemia,hyperlipidemia, obesity, coagaulopathy, hypertension, atherosclerosis,and other disorders related to Syndrome X and cardiovascular diseases.In addition, the compounds can be associated with fewer clinical sideeffects than compounds currently used to treat these conditions.Further, compounds of this invention can be useful for loweringfibrinogen, increasing HDL levels, treating renal disease, controllingdesirable weight, treating demyelinating diseases, treating certainviral infections, and treating liver disease.

DETAILED DESCRIPTION OF THE INVENTION

The terms used to describe the instant invention have the followingmeanings herein.

As used herein, alkyl groups include straight chained and branchedhydrocarbons, which are completely saturated.

Cycloalkyl groups, as used herein, include cyclic hydrocarbons, whichare completely saturated.

As used herein, the term “halo” means Cl, F, or Br. Especially preferredhalo groups are Cl and F.

An especially preferred trihalomethyl group is —CF₃.

As used herein, when Q is a single bond means that Q is absent and the—C(R30)(R40) group is directly bonded to the phenyl.

As used herein, when arylalkyl is arylC₀alkyl, then the aryl group isbonded directly to the group to which the arylalkyl group is bonded. Forexample (but not limited to), if aryl is phenyl then arylC₀alkyl means aphenyl group and arylC₁alkyl means a benzyl.

As used herein, aryl groups include carbocyclic aromatic ring systems(e.g. phenyl), fused polycyclic aromatic ring systems (e.g. naphthyl andanthracenyl) and aromatic ring systems fused to carbocyclic non-aromaticring systems (e.g., 1,2,3,4-tetrahydronaphthyl and benzodioxyl). Oneespecially preferred aryl group is phenyl.

Heterocyclic and heterocyclo group, as used herein, is a ring systemhaving at least one heteroatom such as nitrogen, sulfur or oxygen.Heterocyclic/heterocyclo groups include benzofuranyl, benzothiazolyl,benzothienyl, isoquinolyl, isoxazolyl, morpholino, oxadiazolyl, pyridyl,pyrimidinyl, pyrrolyl, quinolyl, tetrahydropyranyl, dioxaborolan-2-yland thienyl.

Suitable substituents when at least one of said R5, R6, R9 and R19 issubstituted is one or more independently selected from the groupconsisting halo, —(O)—(C₁–C₅)alkylCOOH, C₁–C₅alkyl, and CF₃. When R19 issubstituted, it is preferred that there are from 1–3 substitutions onsaid R19 group. When R9, R5 or R6 are substituted, it is especiallypreferred that there are 1 or 2 independent substituents on said R9, R5or R6 group.

As used herein, the phrase “selectively modulate” means a compound whoseEC50 for the stated PPAR receptor is at least ten fold lower than itsEC50 for the other PPAR receptor subtypes.

When a compound represented by Structural Formula I has more than onechiral substituent it may exist in diastereoisomeric forms. Thediastereoisomeric pairs may be separated by methods known to thoseskilled in the art, for example chromatography or crystallization andthe individual enantiomers within each pair may be separated usingmethods familiar to the skilled artisan. The present invention includeseach diastereoisomer of compounds of Structural Formula I and mixturesthereof.

Certain compounds of Structural Formula I may exist in different stableconformational forms that may be separable. Torsional asymmetry due torestricted rotation about an asymmetric single bond, for example becauseof steric hindrance or ring strain, may permit separation of differentconformers. The present invention includes each conformational isomer ofcompounds of Structural Formula I and mixtures thereof.

Certain compounds of Structural Formula I may exist in zwitterionic formand the present invention includes each zwitterionic form of compoundsof Structural Formula I and mixtures thereof.

“Pharmaceutically-acceptable salt” refers to salts of the compounds ofthe Structural Formula I that are generally clinically acceptable foruse in mammals. Typical pharmaceutically-acceptable salts include thosesalts prepared by reaction of the compounds of the present inventionwith a mineral or organic acid or an organic or inorganic base. Suchsalts are known as base addition salts, respectively. It should berecognized that the particular counterion forming a part of any salt ofthis invention is not of a critical nature, so long as the salt as awhole is pharmaceutically-acceptable and as long as the counterion doesnot contribute undesired qualities to the salt as a whole. These saltsmay be prepared by methods known to those skilled in the art.

The term, active ingredient means the compounds generically described byStructural Formula I as well as the salts of such compounds.

The term pharmaceutically acceptable means that the carrier, diluent,excipients and salt must be compatible with the other ingredients of thecomposition, and having acceptable safety profile for use in a mammal.It is preferred that such mammal is a human patient. Pharmaceuticalcompositions of the present invention are prepared by procedures knownin the art using well-known and readily available ingredients.

Preventing refers to reducing the likelihood that the recipient willincur or develop any of the pathological conditions described herein.The term preventing is particularly applicable to a patient that issusceptible to the particular patholical condition.

Treating refers to mediating a disease or condition and preventing, ormitigating, its further progression or ameliorate the symptomsassociated with the disease or condition.

“Pharmaceutically-effective amount” means that amount of a compound, orof its salt thereof, that will elicit the biological or medical responseof a tissue, system, or mammal. Such an amount can be administeredprophylactically to a patient thought to be susceptible to developmentof a disease or condition. Such amount when administeredprophylactically to a patient can also be effective to prevent or lessenthe severity of the mediated condition. Such an amount is intended toinclude an amount sufficient to modulate a selected PPAR receptor or toprevent or mediate a disease or condition. Generally, the effectiveamount of a Compound of Formula I will be between 0.02 through 5000 mgper day. Preferably 1 through 1,500 mg per day. The desired dose may bepresented in a single dose or as divisded doses administered atappropriate intervals.

A “mammal” is an individual animal that is a member of the taxonomicclass Mammalia. The class Mammalia includes humans, monkeys,chimpanzees, gorillas, cattle, swine, horses, sheep, dogs, cats, mice,and rats.

Administration to a human is most preferred. The compounds andcompositions of the present invention are useful for the treatmentand/or prophylaxis of cardiovascular disease, for raising serum HDLcholesterol levels, for lowering serum triglyceride levels and for lowerserum LDL cholesterol levels. Elevated triglyceride and LDL levels, andlow HDL levels, are risk factors for the development of heart disease,stroke, and circulatory system disorders and diseases.

The compounds and compositions of the present invention can also beuseful for treating and/or preventing obesity.

Further, these compounds and compositions can be useful for thetreatment and/or prophylaxis of non-insulin dependent diabetes mellitus(NIDDM) with reduced or no body weight gains by the patients.Furthermore, compounds and compositions of the present invention can beuseful to treat or prevent acute or transient disorders in insulinsensitivity, such as sometimes occur following surgery, trauma,myocardial infarction, and the like. Additionally, compounds of thisinvention can be useful for treating certain autoimmune conditions. Thephysician of ordinary skill will know how to identify humans who willbenefit from administration of the compounds and compositions of thepresent invention.

The present invention further provides a method for the treatment and/orprophylaxis of hyperglycemia in a human or non-human mammal whichcomprises administering an effective, non-toxic amount of a compound ofthe general formula (I), or a tautomeric form thereof and/or apharmaceutically acceptable salt thereof to a hyperglycemic human ornon-human mammal in need thereof.

The invention also relates to the use of a compound of Formula I asdescribed above, for the manufacture of a medicament for treating a PPARreceptor mediated condition.

A therapeutically effective amount of a compound of Structural Formula Ican be used for the preparation of a medicament useful for treatingSyndrome X, diabetes, treating obesity, lowering tryglyceride levels,lowering serum LDL levels, raising the plasma level of high densitylipoprotein, and for treating, preventing or reducing the risk ofdeveloping atherosclerosis, and/or for preventing or reducing the riskof having a first or subsequent atherosclerotic disease event inmammals, particularly in humans. In general, a therapeutically effectiveamount of a compound of the present invention typically reduces serumtriglyceride levels of a patient by about 20% or more, and increasesserum HDL levels in a patient. It is especially preferred that HDLlevels will be increased by about 30% or more. In adition, atherapeutically effective amount of a compound, used to prevent or treatNIDDM, typically reduces serum glucose levels, or more specificallyHbAlc, of a patient by about 0.7% or more.

Advantageously, compositions containing the compound of StructuralFormula I or the salts thereof may be provided in dosage unit form,preferably each dosage unit containing from about 1 to about 500 mg beadministered although it will, of course, readily be understood that theamount of the compound or compounds of Structural Formula I actually tobe administered will be determined by a physician, in the light of allthe relevant circumstances.

When used herein Syndrome X includes pre-diabetic insulin resistancesyndrome and the resulting complications thereof, insulin resistance,non-insulin dependent diabetes, dyslipidemia, hyperglycemia obesity,coagulopathy, hypertension and other complications associated withdiabetes. The methods and treatments mentioned herein include the aboveand encompass the treatment and/or prophylaxis of any one of or anycombination of the following: pre-diabetic insulin resistance syndrome,the resulting complications thereof, insulin resistance, Type II ornon-insulin dependent diabetes, dyslipidemia, hyperglycemia, obesity andthe complications associated with diabetes including cardiovasculardisease, especially atherosclerosis.

The compositions are formulated and administered in the same generalmanner as detailed herein. The compounds of the instant invention may beused effectively alone or in combination with one or more additionalactive agents depending on the desired target therapy. Combinationtherapy includes administration of a single pharmaceutical dosagecomposition which contains a compound of Structural Formula I and one ormore additional active agents, as well as administration of a compoundof Structural Formula I and each active agent in its own separatepharmaceutical dosage formulation. For example, a compound of StructuralFormula I or salt thereof and an insulin secretogogue such asbiguanides, thiazolidinediones, sulfonylureas, insulin, or α-glucosidoseinhibitors can be administered to the patient together in a single oraldosage composition such as a tablet or capsule, or each agentadministered in separate oral dosage formulations. Where separate dosageformulations are used, a compound of Structural Formula I and one ormore additional active agents can be administered at essentially thesame time, i.e., concurrently, or at separately staggered times, i.e.,sequentially; combination therapy is understood to include all theseregimens.

An example of combination treatment or prevention of atherosclerosis maybe wherein a compound of Structural Formula I or salts thereof isadministered in combination with one or more of the following activeagents: antihyperlipidemic agents; plasma HDL-raising agents;antihypercholesterolemic agents, fibrates, vitamins, aspirin, and thelike. As noted above, the compounds of Structural Formula I can beadministered in combination with more than one additional active agent.

Another example of combination therapy can be seen in treating diabetesand related disorders wherein the compounds of Structural Formula I,salts thereof can be effectively used in combination with, for example,sulfonylureas, biguanides, thiazolidinediones, α-glucosidase inhibitors,other insulin secretogogues, insulin as well as the active agentsdiscussed above for treating atherosclerosis.

The compounds of the present invention, and the pharmaceuticallyacceptable salts, have valuable pharmacological properties and can beused in pharmaceutical compositions containing a therapeuticallyeffective amount of a compound of the present invention, orpharmaceutically acceptable salts thereof, in combination with one ormore pharmaceutically acceptable excipients. Excipients are inertsubstances such as, without limitation, carriers, diluents, fillers,flavoring agents, sweeteners, lubricants, solubilizers, suspendingagents, wetting agents, binders, disintegrating agents, encapsulatingmaterial and other conventional adjuvants. Proper formulation isdependent upon the route of administration chosen. Pharmaceuticalcompositions typically contain from about 1 to about 99 weight percentof the active ingredient that is a compound of the present invention.

Preferably, the pharmaceutical formulation is in unit dosage form. A“unit dosage form” is a physically discrete unit containing a unit dose,suitable for administration in human subjects or other mammals. Forexample, a unit dosage form can be a capsule or tablet, or a number ofcapsules or tablets. A “unit dose” is a predetermined quantity of theactive compound of the present invention, calculated to produce thedesired therapeutic effect, in association with one or morepharmaceutically-acceptable excipients. The quantity of activeingredient in a unit dose may be varied or adjusted from about 0.1 toabout 1000 milligrams or more according to the particular treatmentinvolved.

The dosage regimen utilizing the compounds of the present invention isselected by one of ordinary skill in the medical or veterinary arts, inview of a variety of factors, including, without limitation, thespecies, age, weight, sex, and medical condition of the recipient, theseverity of the condition to be treated, the route of administration,the level of metabolic and excretory function of the recipient, thedosage form employed, the particular compound and salt thereof employed,and the like.

Preferably, the compounds of the present invention are administered in asingle daily dose, or the total daily dose may be administered individed doses, two, three, or more times per day. Where delivery is viatransdermal forms, of course, administration is continuous.

Suitable routes of administration of pharmaceutical compositions of thepresent invention include, for example, oral, eyedrop, rectal,transmucosal, topical, or intestinal administration; parenteral delivery(bolus or infusion), including intramuscular, subcutaneous,intramedullary injections, as well as intrathecal, directintraventricular, intravenous, intraperitoneal, intranasal, orintraocular injections. The compounds of the invention can also beadministered in a targeted drug delivery system, such as, for example,in a liposome coated with endothelial cell-specific antibody.

Solid form formulations include powders, tablets and capsules.

Sterile liquid formulations include suspensions, emulsions, syrups, andelixirs.

Pharmaceutical compositions of the present invention can be manufacturedin a manner that is itself known, e.g., by means of conventional mixing,dissolving, granulating, dragee-making, levigating, emulsifying,encapsulating, entrapping or lyophilizing processes.

The following pharmaceutical formulations 1 and 2 are illustrative onlyand are not intended to limit the scope of the invention in any way.“Active Ingredient”, refers to a compound according to StructuralFormula I or salts thereof.

Formulation 1

Hard gelatin capsules are prepared using the following ingredients:

Quantity (mg/capsule) Active Ingredient 250 Starch, dried 200 Magnesiumstearate 10 Total 460 mg

Formulation 2

A tablet is prepared using the ingredients below:

Quantity (mg/tablet) Active Ingredient 250 Cellulose, microcrystalline400 Silicon dioxide, fumed 10 Stearic acid 5 Total 665 mgThe components are blended and compressed to form tablets each weighing665 mg.

In yet another embodiment of the compounds of the present invention, thecompound is radiolabelled, such as with carbon-14, or tritiated. Saidradiolabelled or tritiated compounds are useful as reference standardsfor in vitro assays to identify new selective PPAR receptor agonists.

The compounds of the present invention can be useful for modulatinginsulin secretion and as research tools. Certain compounds andconditions within the scope of this invention are preferred. Thefollowing conditions, invention embodiments, and compoundcharacteristics listed in tabular form may be independently combined toproduce a variety of preferred compounds and process conditions. Thefollowing list of embodiments of this invention is not intended to limitthe scope of this invention in any way.

Some prefered characteristics of compounds of formula I are:

-   -   (a) R3 is methyl;    -   (b) R4 is hydrogen;    -   (c) R30 is methyl;    -   (d) R30 is alkoxy;    -   (e) R3 and R4 are each hydrogen;    -   (f) R3 and R4 are each methyl;    -   (g) A is carboxyl;    -   (h) w is —O—;    -   (i) w is —S—;    -   (j) W is —NH—;    -   (k) W is selected from the group consisting of C(O)N(R21),        N(R21), N(R21)CH₂, OCH₂, and SO₂;    -   (l) X is C;    -   (m) X is CH₂C;    -   (n) R9 is methyl;    -   (o) R9 is benzyl;    -   (p) R9 is C₁–C₃alkyl;    -   (q) R10 is hydrogen;    -   (r) R10 is methyl    -   (s) Z is N;    -   (t) Z is O;    -   (u) Y is O;    -   (v) Y is S;    -   (w) Q is O;    -   (x) Q is C;    -   (y) Q is attached to the phenyl ring in a meta orientation with        respect to the W group that is attached to the phenyl ring;    -   (z) Q is attached to the phenyl ring in a para orientation with        respect to the W group that is attached to the phenyl ring;    -   (aa) R5 is methyl;    -   (bb) R5 is C₂–C₄alkyl;    -   (cc) R5 is isopropyl;    -   (dd) R5 is arylalkyl;    -   (ee) R₅ combines with W to form a 6 membered cycloheteroalkyl        ring that is fused to the thiazole or oxazole ring from which        the R5 group originates;    -   (ff) R6 is CF₃;    -   (gg) R6 is an optionally substituted group selected from the        group consisting of trihalomethoxy, (C₁–C₆)alkylNC(O)—,        tetramethyldioxaborolanyl, —C(O)(C₁–C₄)alkyl,        —O—(C₁–C₂)alkyl-CO₂H, aryloxy, arylthio, —C(O)N(C₁–C₆)alkyl,        tetrahydropyranyloxy, morpholinyl, (C₅–C₆)cycloalkyloxy,        (C₅–C₆)heterocyclo-oxy, pyridinyl, pyrimidinyl, pyrazinyl and        aryl(C₀–C₄)alkyl;    -   (hh) R7 is CF₃;    -   (ii) R8 is CF₃;    -   (jj) R7 is halo;    -   (kk) R8 is hydrogen;    -   (ll) T₁ is C;    -   (mm) T₁ is N;    -   (nn) Aryl is a phenyl group;    -   (oo) Heterocyclic group contains on O;    -   (pp) A compound of Formula I that selectively modulates a delta        receptor;    -   (qq) A compound of Formula I that is a PPAR coagaonist that        modulates a gamma receptor and a delta receptor;    -   (rr) A compound of Formula I for use in the treatment of        cardiovascular disease;    -   (ss) A compound of Formula I for use in the treatment of        Syndrome X;    -   (tt) A compound of Formula I for use in the control of obesity;    -   (uu) A compound of Formula I for use in treating diabetes.

(vv) A compound of Formula I that is a PPAR receptor agonist.

-   -   (ww) Preferred compounds of Formula I are selected from the        group consisting of        (4-{1-[4-[2-(2-Chloro-6-fluoro-phenyl)-ethyl]-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethylsulfanyl}-2-methyl-phenoxy)-acetic        acid,        (2-Methyl-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-2-phenyl-ethylsulfanyl}-phenoxy)-acetic        acid,        3-(2-Methyl-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-2-phenyl-ethoxy}-phenyl)-propionic        acid,        (4-{1-[4-[2-(2-Chloro-6-fluoro-phenyl)-ethyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-2-methyl-phenoxy)-acetic        acid,        3-(4-{1-[4-[2-(2-Chloro-6-fluoro-phenyl)-ethyl]-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionic        acid,        (2-Methyl-4-{1-[4-phenethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethylsulfanyl}-phenoxy)-acetic        acid,        (2-Methyl-4-{1-[4-phenethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-phenoxy)-acetic        acid,        3-(2-Methyl-4-{1-[4-phenethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy)-phenyl)-propionic        acid,        (2-Methyl-4-{1-(4-phenyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethylsulfanyl}-phenoxy)-acetic        acid,        3-(2-Methyl-4-{1-[4-phenyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-phenyl)-propionic        acid,        (4-{1-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethylsulfanyl}-2-methyl-phenoxy)-acetic        acid,        (4-{1-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-2-methyl-phenoxy)-acetic        acid,        3-(4-{1-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionic        acid,        3-(4-{1-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethylsulfanyl}-2-methyl-phenyl)-propionic        acid,        (2-Methyl-4-(1-[4-phenylsulfanylmethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethylsulfanyl}-phenoxy)-acetic        acid,        (4-{1-[4-(3,5-Bis-trifluoromethyl-phenoxymethyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethylsulfanyl}-2-methyl-phenoxy)-acetic        acid,        (4-{1-[4-(2-Chloro-6-fluoro-phenoxymethyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethylsulfanyl}-2-methyl-phenoxy)-acetic        acid,        3-(4-{1-[4-(3,5-Bis-trifluoromethyl-phenoxymethyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionic        acid,        3-(4-{1-[4-(2-Chloro-6-fluoro-phenoxymethyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionic        acid,        3-(2-Methyl-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-phenyl)-propionic        acid,        3-(2-Methyl-4-{2-[5-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-propoxy}-phenyl)-propionic        acid,        3-(2-Methyl-4-{2-methyl-2-[5-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-propoxy}-phenyl)-propionic        acid,        3-(2-Methyl-4-{2-methyl-2-[5-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-propoxy}-phenyl)-propionic        acid,        3-(2-Methyl-4-{2-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-propoxy}-phenyl)-propionic        acid,        (R)-3-(2-Methyl-4-[2-[5-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-propylsulfanyl)-phenyl)-propionic        acid,        (4-{1R-[4-[2-(2-Chloro-6-fluoro-phenyl)-ethyl]-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethylsulfanyl}-2-methyl-phenoxy)-acetic        acid,        _(4-{1S-[4-[2-(2-Chloro-6-fluoro-phenyl)-ethyl]-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethylsulfanyl}-2-methyl-phenoxy)-acetic        acid,        (2-Methyl-4-{1S-[4-phenethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-phenoxy)-acetic        acid,        (2-Methyl-4-({R-[4-phenethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-phenoxy)-acetic        acid,        _(2-Methyl-4-{1R-[4-phenethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethylsulfanyl}-phenoxy)-acetic        acid,        (R)-(4-{1-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethylsulfanyl}-2-methyl-phenoxy)-acetic        acid,        (S)-(4-{1-(4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethylsulfanyl}-2-methyl-phenoxy)-acetic        acid,        (S)-(4-{1-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-2-methyl-phenoxy)-acetic        acid,        (R)-(4-{1-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-2-methyl-phenoxy)-acetic        acid,        (S)-3-(4-{1-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionic        acid,        (R)-3-(4-{1-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionic        acid,        (R)-3-(4-{1-[4-(2-Chloro-6-fluoro-phenoxymethyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionic        acid,_        (S)-3-(4-{1-[4-(2-Chloro-6-fluoro-phenoxymethyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionic        acid,        (R)-(4-{1-[4-(2-Chloro-6-fluoro-phenoxymethyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethylsulfanyl}-2-methyl-phenoxy)-acetic        acid,        (S)-(4-{1-[4-(2-Chloro-6-fluoro-phenoxymethyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethylsulfanyl}-2-methyl-phenoxy)-acetic        acid,        (S)-(2-Methyl-4-{1-[4-phenylsulfanylmethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethylsulfanyl}-phenoxy)-acetic        acid,        (R)-(2-Methyl-4-{1-[4-phenylsulfanylmethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethylsulfanyl}-phenoxy)-acetic        acid,        _(R)-3-(2-Methyl-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-phenyl)-propionic        acid,        (S)-3-(2-Methyl-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-phenyl)-propionic        acid,        3-(4-{1-[4-Ethyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionic        acid,        (4-{1-[4-Ethyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethoxy}-2-methyl-phenoxy)-acetic        acid,        (4-{1-[4-Ethyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethylsulfanyl}-2-methyl-phenoxy)-acetic        acid,        (4-{1R-[4-Ethyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethylsulfanyl}-2-methyl-phenoxy)-acetic        acid,        (4-{1S-[4-Ethyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethylsulfanyl}-2-methyl-phenoxy)-acetic        acid,        3-(2-Methyl-4-{1S-[4-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-2-phenyl-ethoxy}-phenyl)-propionic        acid,        3-(2-Methyl-4-{1R-[4-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl)-2-phenyl-ethoxy}-phenyl)-propionic        acid,        3-(2-Methyl-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethoxy}-phenyl)-propionic        acid,        3-(2-Methyl-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-propoxy}-phenoxy)-acetic        acid,        3-(2-Methyl-4-{1-(4-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-propoxy}-phenyl)-propionic        acid,        3-(2-Methyl-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-but-3-enyloxy}-phenyl)-propionic        acid,        3-(2-Methyl-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-pentyloxy}-phenyl)-propionic        acid,        3-(4-{1-[4-tert-Butyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionic        acid,        3-(4-{1-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionic        acid,        3-(4-{2-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-propoxy}-2-methyl-phenyl)-propionic        acid,        (R)-3-(2-Methyl-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethoxy}-phenyl)-propionic        acid,        3-(2-Methyl-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-butoxy}-phenyl)-propionic        acid,        3-[4-(1-{4-Isopropyl-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-oxazol-5-yl}-ethoxy)-2-methyl-phenyl]-propionic        acid methyl ester,        3-(4-{1-[2-(4-Hydroxy-phenyl)-4-isopropyl-oxazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionic        acid methyl ester,        3-(4-{1-[4-Isopropyl-2-(4-methoxy-phenyl)-oxazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionic        acid,        3-(4-{1-[2-(3-Cyclopentyloxy-phenyl)-4-isopropyl-oxazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionic        acid,        3-[4-(1-{4-Isopropyl-2-[3-(tetrahydro-pyran-4-yloxy)-phenyl]-oxazol-5-yl}-ethoxy)-2-methyl-phenyl)-propionic        acid,        3-(4-{1-[2-(4-Cyclopentyloxy-phenyl)-4-isopropyl-oxazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionic        acid,        3-(4-{1-[4-Isopropyl-2-(4-piperidin-1-yl-phenyl)-oxazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionic        acid,        3-(4-{1-[4-Isopropyl-2-(3-piperidin-1-yl-phenyl)-oxazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionic        acid,        3-(4-{1-[4-Isopropyl-2-(3-morpholin-4-yl-phenyl)-oxazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionic        acid,        3-(4-{1-[4-Isopropyl-2-(4-morpholin-4-yl-phenyl)-oxazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionic        acid, and        3-(4-{1-[2-(4-Hexylcarbamoyl-phenyl)-4-isopropyl-oxazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionic        acid.

SYNTHESIS

Compounds of the present invention have been formed as specificallydescribed in the examples. Further, many compounds are prepared as moregenerally using a Mitsunobu protocol (O. Mitsunobu, 1981 Synthesis, p1)and other methods known to the skilled artisan. Alternative synthesismethods may also be effective and known to the skilled artisan.

For example, an intermediate like A is alkylated with an alkyl halidelike agent B in the presence of a base (e.g. K2CO3, Cs2CO3 etc.).Hydrolysis in the presence of aqueous NaOH or LiOH gave the acidproduct.

Alternatively, an intermediate like A is coupled with an alcohol C underMitsunobu reaction condition (DEAD/PPh3, ADDP/Pbu3 etc.). Hydrolysis inthe presence of aqueous NaOH or LiOH gave the acid product:

For the compounds with nitrogen in the linker, reductive aminationprotocol is used, for example:

Suzuki coupling or Stille coupling reactions are used for the synthesisof biaryl compounds:

EXEMPLIFICATION

The Examples provided herein are illustrative of the invention claimedherein and are not intended to limit the scope of the claimed inventionin any way.

Instrumental Analysis

Infrared spectra are recorded on a Perkin Elmer 781 spectrometer. ¹H NMRspectra are recorded on a Varian 400 MHz spectrometer at ambienttemperature. Data are reported as follows: chemical shift in ppm frominternal standard tetramethylsilane on the δ scale, multiplicity(b=broad, s=singlet, d=doublet, t=triplet, q=quartet, qn=quintet andm=multiplet), integration, coupling constant (Hz) and assignment. ¹³CNMR are recorded on a Varian 400 MHz spectrometer at ambienttemperature. Chemical shifts are reported in ppm from tetramethylsilaneon the δ scale, with the solvent resonance employed as the internalstandard (CDCl₃ at 77.0 ppm and DMSO-d₆ at 39.5 ppm). High resolutionmass spectra are obtained on VG ZAB 3F or VG 70 SE spectrometers.

Preparation 1 3-Oxo-5-phenyl-pentanoic acid ethyl ester

Ethyl acetoacetate (2.32 g, 20 mmol) is added to a pre-cold solution ofLDA (2.0 M, 20 mL, 40 mmol) in THF (100 mL) at 0° C. After addition, themixture is stirred for 30 min, then benzyl bromide (3.42 g, 20 mmol) isadded dropwise. After stirred at 0° C. for 30 min, the reaction isquenched by 5 N HCl, extracted with ethyl ether. The combined organiclayers are washed with water and brine until it is neutral.

Concentration and column chromatography gave 1.6 g of the titlecompounds.

The following compounds are made in a similar manner:

Preparation 2 5-(2-Chloro-6-fluoro-phenyl)-3-oxo-pentanoic acid ethylester

Preparation 3 2-Chloro-3-Oxo-5-phenyl-pentanoic acid ethyl ester

To a solution of 3-oxo-5-phenyl-pentanoic acid ethyl ester (1.6 g, 7.76mmol) in methylene chloride (18 mL) is added sulfuryl chloride (1.15 g,8.53 mmol) dropwise. After stirred at room temperature for 6 hours, thereaction mixture is poured into water, extracted with methylenechloride, is washed water and brine, dried over sodium sulfate.Concentration gave the crude title compound, which is used for the nextstep without further purification.

The following compounds are made in a similar manner:

Preparation 4 5-(2-Chloro-6-fluoro-phenyl)-2-chloro-3-oxo-pentanoic acidethyl ester

Preparation 5 2-Chloro-4-methyl-3-oxo-pentanoic acid ethyl ester

Preparation 6 2-(4-Bromo-phenyl)-4-methyl-thiazole-5-carboxylic acidethyl ester

4-Bromo-thiobenzamide (5 g) in toluene is heated at reflux for 1 h in aflask equipped with a Dean-Stark trap. The dry 4-bromo-thioamide (3.4 g,15 mmol) and ethyl 2-chloroacetoacetate (2.71 g, 16.4 mmol) are heatedin ethanol (1000 mL) for overnight. The cooled reaction is concentratedand purified by short path chromatrography. The fractions that containedpure product are concentrated to yield 1.5 g (30.6%) ester as a solid.

Th following thiazoles are made in a similar manner:

Preparation 74-Isoproyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethylester

Preparation 84-Phenethyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acidethyl ester

Preparation 94-[2-(2-Chloro-6-fluoro-phenyl)-ethyl-]2-(trifluoromethyl-phenyl)-thiazole-5-carboxylicacid ethyl ester

Preparation 104-Phenyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethylester

Preparation 114-Phenoxymethyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acidethyl ester

Step A 4-Bromomethyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylicacid ethyl ester

4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethylester (1.6 g, 5.00 mmol) is dissolved into chloroform (50 mL) thenN-bromosuccinimide (1.0 g, 5.5 mmol) and 2,2′-azobisisobutyronitrile(0.412 g, 2.5 mmol) are added and the reaction is heated to reflux. Thereaction is monitored by TLC until no starting material remained. Thereaction is allowed to cool to room temperature, then diluted with morechloroform (100 mL). Water (50 mL) is added and the two phases areseparated. The organic layer is washed with brine, then dried overanhydrous sodium sulfate. The material is then concentrated and furtherpurified using flash column chromatography to yield 1.97 g or 99% yield.

Step B4-Phenoxymethyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acidethyl ester

Phenol (0.518 g, 5.5 mmol) is combined with anhydrous acetonitrile (20mL) and cesium carbonate (2.3 g, 10 mmol) and allowed to stir at roomtemperature under nitrogen. To the reaction is added4-bromomethyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acidethyl ester (1.97 g, 5.00 mmol). The reaction is monitored by TLC untilall of the bromide is consumed. The reaction is diluted with ethyl ether(100 mL), then 0.1N NaOH (50 mL) is added. The two phases are separated,then the organic layer is washed with water (50 mL) and brine (50 mL).The organic layer is dried over anhydrous sodium sulfate, thenconcentrated. The material is further purified using flashchromatography to yield 1.75 g or 86% yield of the product.

The following compounds are made in a similar manner:

Preparation 124-(3,5-Bis-trifluoromethyl-phenoxymethyl)-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylicacid ethyl ester

Preparation 134-(2-Chloro-6-fluoro-phenoxymethyl)-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylicacid ethyl ester

Preparation 144-(4-Bromo-phenylsulfanylmethyl)-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylicacid ethyl ester

Preparation 154-Phenylsulfanylmethyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylicacid ethyl ester

Preparation 16[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methanol

A THF (60 mL) solution of4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethylester (14.9 g, 47.3 mmol) is cooled to 0° C. and a 1M LiAlH₄ (47.3 mL,47.3 mmol) is added slowly. The reaction is warmed to room temperatureslowly, after stirring at room temperature for 2 h, tlc (15%EtOAc/hexane) showed that all the starting ester had been consumed. Thereaction is cooled and carefully quenched with 2.4 mL water, 2.4 mL 5NNaOH and 7 mL water. The light tan solid is filter through celite anddried to give 7.70 g crude product. Recrystallization from methanol gavepure alcohol.

The following compounds are made in a similar manner:

Preparation 17[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methanol

Preparation 184-Phenethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methanol

Preparation 194-[2-(2-Chloro-6-fluoro-phenyl)-ethyl]-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methanol

Preparation 20[4-Phenyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methanol

Preparation 21[4-Phenoxymethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methanol

Preparation 22[4-(2-Chloro-6-fluoro-phenoxymethyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methanol

Preparation 23[4-(3,5-Bis-trifluoromethyl-phenoxymethyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methanol

Preparation 24[4-Phenylsulfanylmethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methanol

Preparation 25[4-(4-Bromo-phenylsulfanylmethyl)-2-(4-trifluoromethyl-Phenyl)-thiazol-5-yl]-methanol

Preparation 26 4-Ethyl-2-(4-trifluoromethylphenyl)-oxazole-5-carboxylicacid methyl ester

To a solution of 4-trifluoromethyl benzoic acid (0.100 g, 0.239 mmole)in methanol (2.0 mL), is added sodium hydroxide (0.093 g, 0.287 mmole)and stirred at room temperature for 2 hours. The mixture is concentratedto dryness in vacuo to give sodium 4-trifluoromethyl-benzoate as a whitesolid. It is then mixed with NH₄OAc (8.329, 107.9 mmole) in glacialacetic acid (500 mL) and heated at 100° C. for 16 hours. After removedthe solvents on rota-vapor, the residue is partitioned between ethylacetate (300 mL) and saturated sodium bicarbonate (300 mL). Extractedthe aqueous layer with ethyl acetate (300 mL) one more time. Thecombined organic is ish with brine (3×500 mL), dried over Na₂SO₄,filtered and concentrated. The crude product is purified bychromatography on silica gel column, gradient elute with 0 to 10% ethylacetate in hexane and concentrated to provide the titled compound as awhite solid. Mass [EI+] 300 (M⁺+H).

Preparation 27[4-Ethyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-methanol

To a solution of4-Ethyl-2-(4-trifluoromethyl-phenyl)-oxazole-5-carboxylic acid methylester (4.63 g, 15.47 mmole) in THF (100 mL), is added LiBH₄ in oneportion at 0° C. The reaction is warmed up to room temperature andstirred for an hour. Additional LiBH₄ is added and the reaction isheated at 60° C. for 30 minutes. The excess amount of LiBH₄ is destroyedusing 6N HCl (50 mL) dropwise at 0° C. The mixture is partitionedbetween ethyl acetate (300 mL) and brine (300 mL). The organic layer iswashed with brine (3×300 mL), dried over Na₂SO₄, filtered andconcentrated. The crude product is purified by flash chromatography,eluting with 60% ethyl acetate in hexane and concentrated to provide thetitled compound as a white solid. Mass [EI+] 272 (M+H)⁺.

Preparation 281-[4-Ethyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethanol

Step A 4-Ethyl-2-(4-trifluoromethyl-phenyl)-oxazole-5-carbaldehyde

To a solution of oxalyl chloride (2.0M/DCM, 3.52 mL, 7.04 mmloe) in DCM(50 mL), is injected DMSO (0.998 mL, 14.1 mmole) and stirred for 15minute at −78° C. A solution of[4-Ethyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-methanol (1.59 g,5.86 mmole) in DCM (10 mL) is then added. After stirred for 30 minutes,triethyl amine (4.08 mL, 29.3 mmole) is added. The reaction is kept at−78° C. for another 30 minutes, then warmed up to room temperature for 2hours, washed with brine (3×50 mL), dried over Na₂SO₄, filtered andconcentrated. The crude product is purified by flash chromatography(silica gel, 10% ethyl acetate in hexane) and concentrated to providethe titled compound as a white solid. Mass [EI+] 270 (M+H)⁺.

Step B 1-[4-Ethyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethanol

To a solution of4-ethyl-2-(4-trifluoromethyl-phenyl)-oxazole-5-carbaldehyde (0.793 g,2.95 mmole) in THF (30 mL) at 0° C., is added a solution of methylmagnesium bromide in diethyl ether (3.0M, 2.0 mL, 0.60 mmole) dropwise.The reaction is stirred for 5 minutes and then warmed up to roomtemperature for 30 minutes. The reaction is quenched with NH₄Cl_((aq))(10 mL), partitioned between ethyl acetate (50 mL) and water (50 mL).Extracted the aqueous layer with ethyl acetate (2×50 mL). The combinedorganic is washed with brine (3×100 mL), dried over Na₂SO₄, filtered andconcentrated to provide the titled compound as a white solid. The crudeproduct is used for the next step without further purification. Mass[EI+] 286 (M+H)⁺.

Preparation of 291-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethanol

Step A 4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carbaldehyde

A mixture of[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methanol (5.0 g,18.3 mmol) and MnO2 (2.4 g, 27.5 mmol) in chloroform (110 mL) are heatedto reflux for 48 hrs, cooled to room temperature, filtered throughcelite. Concentration gave 5 gram of the title compound.

Step B 1-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethanol

To a solution of4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carbaldehyde (1.5 g,5.53 mmole) in THF (50 mL) at 0° C., is added a solution of methylmagnesium bromide in diethyl ether (3.0M, 2.0 mL, 6.0 mmole) dropwise.The reaction is stirred for 5 minutes and then warmed up to roomtemperature for 2 hrs. The reaction is quenched with NH₄Cl_((aq)) (10mL), partitioned between ethyl ether (50 mL) and water (50 mL).Extracted the aqueous layer with ethyl ether (2×50 mL). The combinedorganic is washed with brine (3×100 mL), dried over Na₂SO₄, filtered andconcentrated. Column chromatography on silica gel gave 1.35 gram of thetitle compound.

The following compounds are made in a similar manner:

Preparation of 301-[4-isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethanol

Preparation of 311-[4-Phenethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethanol

Preparation of 321-[4-[2-(2-Chloro-6-fluoro-phenyl)-ethyl]-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethanol

Preparation of 331-[4-Phenylsulfanylmethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethanol

Preparation of 341-[4-(2-Chloro-6-fluoro-phenoxymethyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethanol

Preparation of 351-[4-(3,5-Bis-trifluoromethyl-phenoxymethyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethanol

Preparation 361-[4-Phenyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethanol

Preparation 371-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-2-phenyl-ethanol

To a solution of4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carbaldehyde (0.5 g,1.84 mmole) in THF (20 mL) at 0° C., is added a solution of benzylmagnesium chloride in tetrahedronfuran (2.0M, 1.0 mL, 2 mmole) dropwise.The reaction is stirred for 5 minutes and then warmed up to roomtemperature for 2 hrs. The reaction is quenched with NH₄Cl_((aq)),partitioned between ethyl ether and water. Extracted the aqueous layerwith ethyl ether. The combined organic is washed with brine, dried overNa₂SO₄, filtered and concentrated. Column chromatography on silica gelgave the title compound.

Preparation 38 1-[2-(4-Bromo-phenyl)-4-isopropyl-oxazol-5-yl]-ethanol

Step A 2-(4-Bromo-phenyl)-4-isopropyl-oxazole-5-carboxylic acid ethylester

A solution of 4-bromo-benzoic acid (34.0 g, 0.169 mol) in DMF (450 mL)is treated at ambient temperature portionwise with NaH (6.4 g, 0.16 mol,60% oil dispersion). The suspension is heated to 90° C. and2-choro-4-methyl-3-oxo-pentanoic acid ethyl ester (27.7 g, 0.144 mol) isadded neat. The remaining chloride is washed into the reaction flaskusing DMF (25 mL). The reaction mixture is stirred for 18 h, cooled, andtreated with water (600 mL). The mixture is extracted with EtOAc (750mL). The organic layer is washed with brine (2×250 mL), dried (Na₂SO₄),and concentrated to a foam (56 g). This diester is dissolved in aceticacid (500 mL), treated at ambient temperature with ammonium acetate (80g, 1.0 mol)₁ and heated at 120° C. for 20 h. The reaction mixture iscooled, concentrated, and partitioned between EtOAc (500 mL) andsaturated NaHCO₃ solution (3×125 mL). The organic layer is dried(Na₂SO₄), and concentrated. The crude product is purified by silica gelflash chromatography using hexanes:ethyl acetate (6:1) to give the titlecompound (26.6 g, 55%).

Step B [2-(4-Bromo-phenyl)-4-isopropyl-oxazol-5-yl]-methanol

A solution of 2-(4-bromo-phenyl)-4-isopropyl-oxazole-5-carboxylic acidethyl ester (20.6 g, 60.9 mmol) in THF (300 mL) is cooled in anice-water bath and treated portionwise with LiAlH₄ (2.8 g, 73 mmol). Thereaction is complete after 1.5 h. Ice chips (˜10 g) are added to quenchthe excess hydride reagent, and anhydrous Na₂SO₄ (˜50 g) is added. Thethick suspension is stirred 30 min, filtered through celite, and washedwith THF (600 mL). The filtrate is dried (Na₂SO₄) and concentrated. Thecrude product is purified by silica gel flash chromatography usinghexanes:ethyl acetate (3:1) to give a white solid (17.9 g, 99%).

Step C 2-(4-Bromo-phenyl)-4-isopropyl-oxazole-5-carbaldehyde

A solution of [2-(4-bromo-phenyl)-4-isopropyl-oxazol-5-yl]-methanol(17.9 g, 60.4 mmol) in CH₂Cl₂ (450 mL) is treated at ambient temperaturewith acetic acid 1,1-diacetoxy-3-oxo-1·⁵-ioda-2-oxa-indan-1-yl ester (39g, 92 mmol, Dess Martin reagent). The suspension is stirred 1 h and ispartitioned between 10% aqueous Na₂S₂O₃ solution (250 mL) and CH₂Cl₂(150 mL). The organic layer is washed with saturated NaHCO₃ (2×250 mL),and the combined aqueous layers are back-extracted with Et₂O (300 mL).The combined organic layers are dried (Na₂SO₄) and concentrated. Thecrude product is purified by silica gel flash chromatography usinghexanes:ethyl acetate (6:1) to give an offwhite solid (14.4 g, 81%).

Step D 1-[2-(4-Bromo-phenyl)-4-isopropyl-oxazol-5-yl]-ethanol

A solution of 2-(4-bromo-phenyl)-4-isopropyl-oxazole-5-carbaldehyde(14.4 g, 84.9 mmol) in THF (300 mL) is cooled to −78° C. and treateddropwise with methyl magnesium bromide (25 mL, 75 mmol, 3M Et₂O). After1 h, more methyl magnesium bromide (12 mL, 36 mmol) is added. Thereaction mixture is stirred 1.5 h, and saturated NH₄Cl solution (10 ml)is added dropwise. The mixture is partitioned between saturated NH₄Clsolution (10 ml), 1N HCl (25 mL), and Et₂O (300 mL). The organic layeris washed with brine (150 mL), dried (Na₂SO₄), and concentrated. Thecrude product is purified by silica gel flash chromatography usinghexanes:ethyl acetate (9:1 to 5:1) to give an offwhite solid (9.5 g,63%).

Preparation 39 1-[2-(-bromo-phenyl)-4-isopropyl-oxazol-5-yl]-ethanol

By the sequence above as preparation 38, 4-bromo-benzoic acid isconverted to 1-[2-(4-bromo-phenyl)-4-isopropyl-oxazol-5-yl]-ethanol.

-   2-(3-Bromo-phenyl)-4-isopropyl-oxazole-5-carboxylic acid ethyl    ester: 135 mmol scale, 35%-   [2-(3-Bromo-phenyl)-4-isopropyl-oxazol-5-yl]-methanol: 45 mmol    scale, 100%-   2-(3-Bromo-phenyl)-4-isopropyl-oxazole-5-carbaldehyde: 45 mmol, 69%-   1-[2-(3-Bromo-phenyl)-4-isopropyl-oxazol-5-yl]-ethanol: 29 mmol    scale, 100%

Preparation 401-[4-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethanol

Step 1 2-(4-tert-Butyl-benzoylamino)-propionic acid methyl ester

D,L Alanine methyl ester (18.5 g, 132 mmol), triethylamine (42 mL, 300mmol) and dichloromethane (300 mL) are stirred in an ice/water bath.4-(Trifluromethyl)benzoyl chloride (25 g, 120 mmol) is added dropwiseand the resulting mixture is allowed to stir for 20 hr at roomtemperature. 500 mL water and 100 mL 1M hydrochloric acid aresuccessively added. The organic layer is separated, washed with 250 mLeach of saturated sodium hydrogen carbonate, water, and brine, driedover anhydrous magnesium sulfate, filtered, and concentrated to 100 mLvolume. The mixture is diluted with 200 mL hexanes, cooled to 0° C. for1 hr, and the white solid filtered and dried under vacuum to afford2-(4-tert-Butyl-benzoylamino)-propionic acid methyl ester, 26.5 g, 80%.MS (ES): 276 (M⁺+1).

Step 2 2-(4-tert-Butyl-benzoylamino)-propionic acid

A mixture of 2-(4-tert-Butyl-benzoylamino)-propionic acid methyl ester(26.3 g, 95.6 mmol), 200 mL 1M sodium hydroxide, and 100 mLtetrahydrofuran is stirred at room temperature 20 hr. The resultingclear solution is cooled on an ice/water bath and the pH is adjusted to2 with concentrated hydrochloric acid. The product is extracted withthree 250 mL portions of ethyl acetate. The combined extracts are washedwith 100 mL each of water and brine, dried over anhydrous magnesiumsulfate, filtered, and concentrated to afford2-(4-tert-Butyl-benzoylamino)-propionic acid as a white solid, 24.6 g,95%. MS M⁺+1 260.

Step 3 [4-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-methanol

To a solution of 2-(4-Trifluoromethyl-benzoylamino)-propionic acid (33.4g, 128 mmol) is added oxalyl chloride (111 mL, 1.27 Mol) and 1 drop ofDMF and the solution stirred overnight. The volatiles are removed invacuo and toluene (20 mL) is added. The toluene is then removed invacuo. To the resultant crude oil is dissolve in 50 mL methylenechloride, cooled to 0° C. and triethylamine (27 mL, 192 mmol) is addedfollowed by methanol (50 mL). After 3 hrs the volatiles are removed invacuo and the crude oil is purified by flash column chromatography(20%–50% ethyl acetate/hexanes) to provide 12.6 g (35%) of4-Methyl-2-(4-trifluoromethyl-phenyl)-oxazole-5-carboxylic acid methylester. This ester (2.0 g, 7.0 mmol) is reduced to the alcohol bydissolution in THF (50 mL) and adding 4 eq. LiBH₄ (0.610 g, 28.0 mmol)to provide 1.8 g (100%)[4-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-methanol. MS M⁺+1258.

Step 4

4-Methyl-2-(4-trifluoromethyl-phenyl)-oxazole-5-carbaldehyde[4-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-methanol (2.42 g,9.41 mmol) and 100 mL dichloromethane are stirred at room temperature.Dess-Martin periodinane (8.0 g, 18.8 mmol) is added and the resultingmixture is stirred 4 hr at room temperature. The mixture is diluted with100 mL saturated sodium hydrogen carbonate. The organic layer isseparated, washed with 50 mL each of water and brine, dried overanhydrous magnesium sulfate, filtered, and concentrated. The crudeproduct is purified by silica gel chromatography eluting with a mixtureof 8:2 hexanes:ethyl acetate affording4-methyl-2-(4-trifluoromethyl-phenyl)-oxazole-5-carbaldehyde as a whitesolid, 2.12 g, 89%. MS (M⁺+1) 256.

Step 5 1-[4-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethanol

A solution of4-methyl-2-(4-trifluoromethyl-phenyl)-oxazole-5-carbaldehyde (1.32 g,5.16 mmol) and 50 mL tetrahydrofuran is stirred at 0° C. Methylmagnesium bromide (2.2 mL, 6.71 mmol, 3M) is added dropwise and theresulting mixture is allowed to stir at room temperature 30 min. Thereaction is not complete, so an additional amound of methyl magnesiumbromide (1 mL, 3 mmol) is added and the reaction stirred an additional 1hr at room temperature. The mixture is cooled on an ice/water bath andaqueous ammonium chloride (10 mL) is added. The product is extractedwith three 75 mL portions of ethyl acetate, the combined extracts aredried over anhydrous magnesium sulfate, filtered and concentrated. Thecrude product is purified by silica gel chromatography eluting with amixture of 1:1 hexanes:ethyl acetate to afford1-[4-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethanol as anivory solid, 1.12 g, 80%. MS (M⁺+1) 272.

Preparation 412-Methyl-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-propan-1-ol

This compound is prepared in analogous fashion using preparation 40.Steps 1–4 are identical as previously described. Step 5 is performedusing isoproyl magnesium bromide to afford2-methyl-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-propan-1-ol.

Preparation 421-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethanol

Step 1 2-chloro-4-methyl-3-oxo-pentanoic acid ethyl ester

ethyl isobutyryl acetate (12.0 g, 75.85 mmol) is stirred at 0° C. indichloromethane (75 mL). Sulfuryl chloride (6.5 mL, 80 mmol) is addeddropwise and the resulting mixture is allowed to stir 20 hr at roomtemperature. The reaction mixture is cooled to 0° C. and aqueoussaturated sodium hydrogen carbonate (200 mL) is added cautiously. Thelayers are separated, the aqueous layer is washed with dichloromethane(100 mL), the combined organic layers are washed with water and brine(100 mL each), dried over anhydrous magnesium sulfate, filtered, andconcentrated to constant weight to give2-chloro-4-methyl-3-oxo-pentanoic acid ethyl ester as a colorless oil,14.6 g, 100%. MS (M⁺+1) 193.

Step 2 4-Isopropyl-2-(4-trifluoromethyl-phenyl)-oxazole-5-carboxylicacid ethyl ester

Sodium Hydride, 60% mineral oil (1.9 g, 46.3 mmol) and dimethylformamide(50 mL) are stirred at room tmperature and 4-(trifluoromethyl)benzoicacid (8.0 g, 42.1 mmol) is added. To the resulting slurry is added2-chloro-4-methyl-3-oxo-pentanoic acid ethyl ester (8.5 g, 44.2 mmol)and the resulting mixture is heated to 90° C. for 3 hr. The reactionmixture is cooled, diluted with water (100 mL), and product is extractedwith ethyl acetate (100 mL). The organic layer is washed with water(three 100 mL portions) and brine (100 mL), dried over anhydrousmagnesium sulfate, filtered, and concentrated to constant weight to give4-trifluoromethyl-benzoic acid 1-ethoxycarbonyl-3-methyl-2-oxo-butylester as a colorless oil, 14.6 g, 100%. The resulting oil is stirred ina mixture of acetic acid (100 mL) and ammonium acetate (9.75 g, 126.5mmol) at reflux 1 hr, then 20 hr at room temperature. The solvent isremoved in vacuo and the residue is partioned between aqueous saturatedsodium hydrogen carbonate (100 mL) and ethyl acetate (100 mL. The layersare separated, the aqueous layer is washed with ethyl acetate (100 mL).The organic extracts are combined, washed with water and brine (100 mLeach) dried over anhydrous magnesium sulfate, filtered, andconcentrated. The residue is purified over silica eluting with 9:1hexanes:ethyl acetate to afford4-Isopropyl-2-(4-trifluoromethyl-phenyl)-oxazole-5-carboxylic acid ethylester as a white solid, 8.1 g, 60%. MS (M⁺+1) 328.

Step 3 [4-Isopropyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-methanol

4-Isopropyl-2-(4-trifluoromethyl-phenyl)-oxazole-5-carboxylic acid ethylester (0.53 g, 1.62 mmol) is stirred in tetrahydrofuran (25 mL) at 0° C.Lithium aluminum hydride (0.122 g, 3.23 mmol) is added and the mixtureis stirred 18 hr at room temperature. The mixture is diluted carefullywith 1M aqueous hydrochloric acid (10 mL), and the product is extractedwith ethyl acetate (three 75 mL portions). The extracts are combined,dried over anhydrous magnesium sulfate, filtered, and concentrated toafford [4-Isopropyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-methanolas a white solid, 0.46 g, 100%. MS (M⁺+1) 286.

Step 4 4-Isopropyl-2-(4-trifluoromethyl-phenyl)-oxazole-5-carbaldehyde

[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-methanol (0.46 g,1.612 mmol), Dess-Martin periodinane (1.36 g, 3.22 mmol) anddichloromethane (25 mL) are stirred 1 hr at room temperature. Themixture is diluted with aqueous saturated sodium hydrogen carbonate (100mL) and dichloromethane (100 mL). The layers are separated, the aqueouslayer is washed with dichloromethane (100 mL). The organic ishes arecombined, washed with brine (50 mL), dried over anhydrous magnesiumsulfate, filtered, and concentrated in vacuo. The product is purifiedover silica eluting with 3:1 hexanes:ethyl acetate to afford4-Isopropyl-2-(4-trifluoromethyl-phenyl)-oxazole-5-carbaldehyde as awhite solid, 0.41 g, 90%. %. MS (M⁺+1) 284.

Step 5 1-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethanol

Followed a similar procedure in step 5 of preparation 40.

Preparation 431-[4-tert-Butyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethanol

This compound is prepared in a similar manner as Preparation 42 usingethyl pivaloyl acetate as starting material at step 1.

Preparation 441-[4-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-propan-1-ol

Step 1 4-methyl-2-(4-trifluoromethyl-phenyl)-oxazole-5-carboxylic acidmethoxy-methyl-amide

To a solution of 2-(4-Trifluoromethyl-benzoylamino)-propionic acid (5.0g, 19.14 mmol) is added oxalyl chloride (16.7 mL, 191.4 mmol) and 2drops of DMF and the solution stirred overnight. The volatiles areremoved in vacuo and toluene (20 mL) is added. The toluene is thenremoved in vacuo. To the resultant crude oil is dissolve indichloromethane (100 mL), cooled to 0° C. and triethylamine (13.4 mL, 96mmol) is added followed by N,O-dimethyl hydroxylamine hydrochloride (9.4g, 96 mmol). After 1 hr the mixture is partioned between 1M aqueoushydrochloric acid and ethyl acetate. The organic layer is dried overanhydrous magnesium sulfate, filtered, concentrated in vacuo. Theproduct is purified over silica eluting with 8:2 hexanes:ethyl acetateto afford 4-methyl-2-(4-trifluoromethyl-phenyl)-oxazole-5-carboxylicacid methoxy-methyl-amide as a white crystalline solid, 2.4 g, 40%. MS(M⁺+1) 315.

Step 21-[4-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-propan-1-one

4-methyl-2-(4-trifluoromethyl-phenyl)-oxazole-5-carboxylic acidmethoxy-methyl-amide (1.0 g, 3.18 mmol) is stirred in tetrahydrofuran(15 mL) at −78° C. ethyl magnesium bromide, 3M/ether (2.1 mL, 4.14 mmol)is added and the mixture is warmed to room temperature. The mixture isdiluted with aqueous saturated ammonium chloride and washed with ethylacetate (three 50 mL portions). The combined ishes are dried overanhydrous magnesium sulfate, filtered and concentrated in vacuo. Theresidue is purified over silica eluting with 7:3 hexanes:ethyl acetateto afford1-[4-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-propan-1-one as anivory solid, 0.70 g, 78%. MS (M⁺+1) 284.

Step 3 1-[4-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-propan-1-ol

1-[4-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-propan-1-one (0.68g, 2.4 mmol) and tetrahydrofuran (5 mL) are stirred at 0° C. Lithiumborohydride (0.14 g, 6.36 mmol) is added and the mixture is stirred 10min at 0° C., and 30 min at room temperature. The mixture is dilutedwith 1M aqueous hydrochloric acid and washed with ethyl acetate (three50 mL portions). The organic ishes are dried over anhydrous magnesiumsulfate, filtered, and concentrated in vacuo. The residue is purifiedover silica eluting with 8:2 hexanes:ethyl acetate to 1:1 hexanes ethylacetate to afford1-[4-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-propan-1-ol asivory solid, 0.69 g, 100%. MS (M⁺+1) 286.

Preparation 451-[4-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-but-3-en-1-ol

This compound is prepared in a similar manner as Preparation 44 usingallyl magnesium bromide in step 2 as reagent.

Preparation 461-[4-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-pentan-1-ol

This compound is prepared in a similar manner as Preparation 44 usingn-butyl lithium in step 2 as reagent.

Preparation 471-[4-Isopropyl-2-(4-trifluoromethoxy-phenyl)-oxazol-5-yl]-ethanol

Preparation 48 1-[2-(4-Bromo-phenyl)-4-isopropyl-oxazol-5-yl]-ethanol

Preparation 492-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-propan-1-ol

Step 1 4-Isopropyl-2-(4-trifluoromethyl-phenyl)-4H-oxazol-5-one

3-Methyl-2-(4-trifluoromethyl-benzoylamino)-butyric acid methyl ester(4.75 g, 16.42 mmol) is dissolved in acetic anhydride (25 mL) and heatedto 95° C. for 3 hr. The mixture is concentrated in vacuo and the residueis partitioned between aqueous saturated sodium hydrogen carbonate (100mL) and ethyl acetate (100 mL) the layers are separated, the organicphase is washed with water and brine (100 mL each), dried over anhydrousmagnesium sulfate, filtered, concentrated in vacuo, and purified oversilica gel eluting with 9:1 hexanes:ethyl acetate to afford4-Isopropyl-2-(4-trifluoromethyl-phenyl)-4H-oxazol-5-one as a colorlessoil which solidifies to a white crystalline solid on standing, 4.14 g,93%. MS (M⁺⁺1) 272.

Step 22-[4-Isopropyl-2-(4-trifluoromethyl-Phenyl)-oxazol-5-yl]-propionic acidethyl ester

4-Isopropyl-2-(4-trifluoromethyl-phenyl)-4H-oxazol-5-one (1.0 g, 3.69mmol) and (carbethoxyethylidine)triphenyl-phosphorane (2.67 g, 7.37mmol) are stirred in toluene (20 mL) at reflux 3 hr. The mixture isconcentrated in vacuo and the residue is purified over silica elutingwith 9:1 hexanes:ethyl acetate affording2-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-propionic acidethyl ester as a pale orange oil, 1.11 g, 85%. MS (M⁺+1) 356.

Step 32-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-propan-1-ol

2-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-propionic acidethyl ester (1.11 g, 3.12 mmol) and tetrahydrofuran (50 mL) are cooledto 0° C. Lithium aluminum hydride (0.24 g, 6.25 mmol) is added and theresulting mixture is stirred 20 hr at room temperature. The mixture iscooled to 0° C. and 1M aqueous hydrochloric acid (50 mL) is carefullyadded. The mixture is then diluted with ethyl acetate (100 mL) and thelayers are separated. The aqueous layer is washed with ethyl acetate(100 mL) and the organic ishes are combined, washed with water and brine(50 mL each), dried over anhydrous magnesium sulfate, filtered andconcentrated to constant weight to give2-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-propan-1-ol asa pale orange oil, 1.03 g, 100%. MS (M⁺+1) 314.

The following compound is made in similar manner:

Preparation 502-[4-Isopropyl-2-(4-trifluoromethoxy-phenyl)-oxazol-5-yl]-propan-1-ol

Preparation 512-[4-Isopropyl-2-(4-phenoxy-phenyl)-oxazol-5-yl]-propan-1-ol

Preparation 522-[2-(4-Bromo-phenyl)-4-isopropyl-oxazol-5-yl]-propan-1-ol

Preparation 532-[5-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-propan-1-ol and2-Methyl-2-[5-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-propan-1-ol

Step A 4-Bromo-2-methyl-3-oxo-pentanoic acid methyl ester and4-Bromo-2,2-dimethyl-3-oxo-pentanoic acid methyl ester

A solution of bromine (18.4 g, 115 mmol) in chloroform (30 mL) is addedto a mixture of 2-methyl-3-oxo-pentanoic acid methyl ester and2,2-dimethyl-3-oxo-pentanoic acid methyl ester (16.5 g) in chloroform(120 mL) at 0–5° C. dropwise. After the addition of bromine, the mixtureis allowed to warm up to room temperature slowly and stirred overnight.The reaction is then quenched by ice water, the layers are separated.The organic layer is washed with cold water and brine, dried over sodiumsulfate. Concentration gave the title compounds, which is used for nextstep without further purification.

Step B 2-[5-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-propionicacid methyl ester and2-Methyl-2-[5-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-propionicacid methyl ester

A mixture of 4-Trifluoromethyl-thiobenzamide (7.70 g, 37.5 mmol) and thecrude product from step A (9.0 g, 40 mmol) in ethanol (500 mL) is heatedto reflux for 4 days. Solvent is evaporated and the residue is purifiedby chromatography on silica gel yielding the title compounds (11 g).

Step C2-[5-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-propan-1-ol and2-Methyl-2-[5-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-propan-1-ol

To a solution of2-[5-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-propionic acidmethyl ester and2-Methyl-2-[5-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-propionicacid methyl ester (10.6 g) in THF (50 mL) is added a solution of lithiumaluminum hydride in THF (1.0 M, 33 mL) at 0° C. After 2 hrs, thereaction is quenched by water and sodium hydroxide, filtered,concentrated. Chromatography on silica gel gave2-[5-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-propan-1-ol (4.3g) and2-Methyl-2-[5-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-propan-1-ol(2.6 g).

Preparation 542-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-propan-1-ol and2-Methyl-2-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-propan-1-ol

Step A 4-Bromo-2-methyl-3-oxo-pentanoic acid methyl ester and4-Bromo-2,2-dimethyl-3-oxo-pentanoic acid methyl ester

A solution of bromine (18.4 g, 115 mmol) in chloroform (20 mL) is addedto a mixture of 2-methyl-3-oxo-pentanoic acid methyl ester and2,2-dimethyl-3-oxo-pentanoic acid methyl ester (ca. 115 mmol) inchloroform (120 mL) at 0–5° C. dropwise. After the addition of bromine,the mixture is allowed to warm up to room temperature slowly and stirredovernight. The reaction is then quenched by ice water, the layers areseparated. The organic layer is washed with cold water and brine, driedover sodium sulfate. Concentration gave the title compounds, which isused for next step without further purification.

Step B 2-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-propionicacid methyl ester and2-Methyl-2-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-propionicacid methyl ester

To a solution of 4-Trifluoromethyl-benzoic acid (7.6 g, 40 mmol) inmethanol (100 mL) is added sodium hydroxide (1.6 g, 40 mmol), stirredfor 30 min, methanol is evaporated. The residue is taken into DMF (50mL) and the crude product from step A (10 g) is added. The mixture isstirred overnight, diluted with ethyl acetate, washed with water andbrine, dried over sodium sulfate, concentrated. The residue is takeninto ethanol (150 mL) and treated with ammonium acetate (6.17 g) andheated at 70° C. for 12 hrs. Ethanol is evaporated, the residue is mixedwith ammonium acetate (12.3 g) in glacial acid (750 mL) and heated at100° C. for 2 days. Solvent is evaporated and the residue is taken intoethyl acetate, washed with water and brine, dried. Chromatography onsilica gel gave2-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-propionic acidmethyl ester (3.40 g) and2-Methyl-2-[S-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-propionicacid methyl ester (2.80 g).

Step C 2-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-propan-1-ol

To a solution of2-[5-methyl-2-(4-trifluoromethyl-phenyl)-ozazol-4-yl]-propionic acidmethyl ester (3.4 g) from step B in THF (20 mL) is added a solution oflithium aluminum hydride in THF (1.0 M, 14 mL) at 0° C. After 2 hrs, thereaction is quenched by water and sodium hydroxide, filtered,concentrated. Chromatography on silica gel gave2-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-propan-1-ol (0.88g).

Step D and2-Methyl-2-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-propan-1-ol

To a solution of2-methyl-2-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-propionicacid methyl ester (2.8 g) from step B in THF (14 mL) is added a solutionof lithium aluminum hydride in THF (1.0 M, 13 mL) at 0° C. After 2 hrs,the reaction is quenched by water and sodium hydroxide, filtered,concentrated. Chromatography on silica gel gave2-Methyl-2-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-propan-1-ol(2.3 g).

Preparation 552-Methyl-2-[5-ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-propan-1-ol

Step A 4-Bromo-2,2-dimethyl-3-oxo-hexanoic acid methyl ester

A solution of bromine (24 g, 150 mmol) in chloroform (30 mL) is added to2,2-dimethyl-3-oxo-hexanoic acid methyl ester (25.9 g, 150 mmol) inchloroform (126 mL) at 0–5° C. dropwise. After the addition of bromine,the mixture is allowed to warm up to room temperature slowly and stirredovernight. The reaction is then quenched by ice water, the layers areseparated. The organic layer is washed with cold water and brine, driedover sodium sulfate. Concentration gave the title compounds (36.9 g),which is used for next step without further purification.

Step B2-Methyl-2-[5-ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-propionicacid methyl ester

A mixture of 4-Trifluoromethyl-thiobenzamide (12.3 g, 60 mmol) and thecrude product from step A (16.6 g, 66 mmol) in ethanol (600 mL) isheated to reflux for 3 days. Solvent is evaporated and the residue ispurified by chromatography on silica gel yielding the title compounds(14.5 g).

Step C2-Methyl-2-[5-ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-propan-1-ol

To a solution of2-Methyl-2-[5-ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-propionicacid methyl ester (14.5 g, 40.6 mmol) in THF (100 mL) is added asolution of lithium aluminum hydride in THF (1.0 M, 41 mL) at 0° C.After 2 hrs, the reaction is quenched by water and sodium hydroxide,filtered, concentrated. Chromatography on silica gel gave2-Methyl-2-[5-ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-propan-1-ol(12.3 g).

Preparation 562-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propan-1-ol

Step A 1-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethanone

A mixture of1-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl-]-ethanol (1.0 g,3.48 mmol) and MnO2 (0.45 g, 5.22 mmol) in chloroform (30 mL) is heatedto reflux, after 24 hrs, additional MnO2 (300 mg) is added and refluxedfor another 9 hrs, the reaction mixture is filtered through celite.Concentration of filtrate gave the title compound (1.0 g).

Step B5-(2-Methoxy-1-methyl-vinyl)-4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole

To a solution of (methoxymethyl)triphenyl phosphonium chloride (15.5 g,45.2 mmole) in toluene (330 mL) is added potassium t-butoxide (5.07 g,45.2 mmole) in one portion and stirred for 30 minutes, then a solutionof 1-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethanone (8.6g, 30.1 mmole) in toluene (20 mL) is added. The reaction is stirred for4 hours, quenched by NH4Cl aqueous solution, extracted with ethylacetate and then concentrated on rota vapor. The residue is purified ona silica gel column, eluting with 0–10% ethyl acetate in hexane andconcentrated to provide the title compound (7.0 g).

Step C2-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propionaldehyde

5-(2-Methoxy-1-methyl-vinyl)-4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole(7.0 g, 22.3 mmol) in THF (200 mL) is treated with concentrated HClaqueous solution (7 mL) at 50° C. for 2 hours. The reaction mixture isdiluted with ethyl acetate, washed with sodium bicarbonate aqueoussolution, dried over sodium sulfate. Concentration and columnchromatography on silica gel provided the title compound (3.5 g).

Step D2-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propan-1-ol

To a solution of2-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propionaldehyde(2.0 g, 6.68 mmol) in ethanol (30 mL) is added to NaBH, (0.25 g, 6.6mmol) in portions at 0° C. The reaction is kept at 0° C. for 15 minutesand warmed up to room temperature for 2 hours. The reaction is quenchedusing water, extracted with ethyl acetate, dried over sodium sulfate.Concentration and column chromatography on silica gel eluted withhexanes and ethyl acetate gave the title compound (2.0 g).

Preparation 572-[5-Ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-propan-1-ol

Step A

3-Oxo-hexanoic acid ethyl ester (29.5 g, 0.1865 Mol) is dissolved intoanhydrous dichloromethane (DCM) (400 mL) and then cooled to 0° C.–5° C.while stirring. A solution of bromine (30.4 g, 0.190 Mol) in DCM (80 mL)is added dropwise over 2 h. to the solution of the beta keto-ester.After the addition, the mixture is allowed to stir 0.5 h. at 0° C., thenthe ice bath is removed and the mixture is allowed to stir at roomtemperature for 18 h. TLC will show complete consumtion of startingmaterial, then ice water (200 g) is added with stirring. The organiclayer is collected and washed with cold water (2×) and brine. Thefiltered solution is dried over anhydrous sodium sulfate, thenconcentrated to a clear liquid. The crude 4-Bromo-3-oxo-hexanoic acidethyl ester (40.2 g, 0.1695 Mol), 91% yield, is used without furtherpurification.

Step B

4-Bromo-3-oxo-hexanoic acid ethyl ester (4.68 g, 20.98 mmol) isdissolved into denatured ethanol (100 mL) and para-trifluoromethylthiobenzamide (4.31 g, 21 mmol) is added in one portion. The reaction ispurged of air and flushed with nitrogen then heated to reflux. Thereaction is monitored by TLC and HPLC and when complete, the reaction isallowed to cool to room temperature. The solvent is removed and thereaction is diluted with ethyl acetate (200 mL), followed by ishes withsaturated sodium bicarbonate solution, water, and brine. The ethylacetate solution is dried over anhydrous sodium sulfate, thenconcentrated and further purified using flash column chromatography (10%EtOAc/Hexanes) to yield pure[5-Ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-acetic acid ethylester (5.09 g, 14.82 mmol) or 71% yield.

Step C

[5-Ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-acetic acid ethylester (2.02 g, 6.13 mmol) is dissolved into anhydrous tetrahydrofuran(THF) (10 mL) and lithium diisopropylamide (LDA) is slowly added at roomtemperature. This solution is allowed to stir at room temperature andmonitored by TLC. After complete conversion, methyl iodide (582 mg, 4.00mmol) is added slowly and the reaction is followed by TLC. After 18 h.,the reaction is not complete, but is quenched with saturated ammoniumchloride solution and diluted with diethyl ether. The two phases areseparated and the organic layer is washed with water and brine, driedover anhydrous sodium sufate, then concentrated and purified using flashcolumn chromatography (10% EtOAc/Hexanes). The pure2-[5-Ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-propionic acidethyl ester (1.30 g, 3.64 mmol) is obtained in 59% yield.

Step D

2-[5-Ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-propionic acidethyl ester (1.05 g, 3.06 mmol) is dissolved into anhydroustetrahydrofuran (THF) (10 mL) and then cooled to 0° C. with stirring.Lithium aluminum hydride (3.10 mL, 1M in THF, 3.10 mmol) is slowly addedby syringe and the reaction is monitored by TLC. Upon completeconversion, the reaction is carefully quenched using water, base, andwater. Celite is added to the reaction, followed by diethyl ether andthe mixture is then filtered through a celite plug. The two phases arethen separated and the organic layer is washed using water and brine.The organic layer is the dried over anhydrous sodium sulfate andconcentrated. The pure2-[5-Ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-propan-1-ol (0.930g, 2.95 mmol) is obtained in 95% yield after flash columnchromatography.

Preparation 582-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propan-1-ol

Step A

4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acidmethyl ester (14 g, 40.1 mmol) is dissolved into anhydroustetrahydrofuran (THF) (200 mL) and then cooled to −30° C. while stirringunder nitrogen. N-methyl, N-methoxy amine hydrochloride (0.881 g, 9.04mmol) is then added to the solution in one portion. Isopropyl magnesiumchloride (8.73 mL, 2M soln. in THF, 17.46 mmol) is slowly added to thecooled suspension over 1 h. TLC will show complete consumtion ofstarting material, then 30% solution of ammonium chloride is added withstirring. The reaction is diluted with diethyl ether and extracted. Theorganic layer is collected and washed with cold water (2×) and brine.The solution is then dried over anhydrous sodium sulfate, filtered, andconcentrated. The4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acidmethoxy-methyl-amide (0.705 g, 1.97 mmol) is obtained in pure form afterflash column chromatography.

Step B

4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acidmethoxy-methyl-amide (7.56 g, 21.09 mmol) is suspended in anhydroustetrahydrofuran (100 mL), and cooled to 0° C. with stirring undernitrogen. Methyl magnesium bromide (28 mL, 3.0M in diethyl ether, 84.36mmol) is slowly added to the reaction over 1 h. The reaction is allowedto warm slowly to room temperature and monitored by TLC. Upon completeconsumption of starting material, the reaction is carefully neutralizedwith 1N hydrochloric acid, extracted with diethyl ether, washed, dried,and concentrated. The1-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethanone (5.4g, 17.23 mmol) 82% yield, is used without further purification.

Step C

(Methoxymethyl)triphenylphosphinium chloride (8.86 g, 25.84 mmol) issuspended in anhydrous toluene (75 mL) and potassium tert-butoxide (2.90g, 25.84 mmol) is carefully added. The solution is allowed to cool andstir at room temperature for 1 h.1-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethanone (5.4g, 17.23 mmol) is then dissolved into anhydrous toluene (25 mL) andadded to the reaction mixture by syringe. The reaction is allowed tostir at room temperature for several hours and is monitored by TLC. Uponcomplete consumption of starting material, the reaction is carefullyquenched with saturated ammonium chloride solution, extracted withdiethyl ether, washed, dried, and concentrated. The4-Isopropyl-5-(2-methoxy-1-methyl-vinyl)-2-(4-trifluoromethyl-phenyl)-thiazoleis used in the next step without further purification.

Step D

4-Isopropyl-5-(2-methoxy-1-methyl-vinyl)-2-(4-trifluoromethyl-phenyl)-thiazoleis dissolved into anhydrous tetrahydrofuran (100 mL) and concentratedhydrochloric acid (5 mL) is added with stirring under nitrogen. Thereaction is heated to 50° C. and monitored by TLC. Upon completeconsumption of starting material, the reaction is carefully neutralizedwith sodium hydroxide, extracted with diethyl ether, washed, dried, andconcentrated. The2-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propionaldehyde(4.6 g, 14.05 mmol), 82% two steps, is obtained in pure form after flashcolumn chromatography.

Step E

2-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propionaldehyde(4.05 g, 12.5 mmol) is dissolved into denatured ethanol (60 mL) at roomtemperature then cooled to 0° C. in an ice bath. Sodium borohydride(0.467 g, 12.5 mmol) is then carefully added in small portions. Thereaction is allowed to warm slowly to room temperature and is monitoredby TLC. Upon complete consumption of starting material, the reaction iscarefully quenched with water and diluted with ethyl acetate. Theethanol is removed and the residue is extracted with ethyl acetate,washed, dried, and concentrated. The2-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propan-1-ol(4.0 g, 12.14 mmol), 97%, is obtained in pure form after flash columnchromatography.

Preparation 59 Toluene-4-sulfonic acid2-[5-ethyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-ethyl ester

Step A

To a solution of •••••-trifluoromethyl-para-toluic acid (5.0 g, 26.3mmol) in anhydrous acetone (100 mL) at 0° C. under nitrogen is added4-bromo-3-oxo-hexanoic acid ethyl ester (6.4 g, 27 mmol) and triethylamine (3.5 mL, 27 mmol). The mixture is allowed to stir 0.5 h. at 0° C.,then the ice bath is removed and the mixture allowed to stir at roomtemperature for 18 h. The reaction is monitored by TLC and HPLC untilcomplete consumtion of starting material, then ice water added withstirring and the mixture is extracted.

The organic layer is collected and washed with brine, then dried overanhydrous sodium sulfate. The crude 4-Trifluoromethyl-benzoic acid3-ethoxycarbonyl-1-ethyl-2-oxo-propyl ester is used in the next stepwithout further purification.

Step B

4-Trifluoromethyl-benzoic acid 3-ethoxycarbonyl-1-ethyl-2-oxo-propylester (25 mmol) is dissolved in acetic acid (100 mL) and dry ammoniumacetate (10 g, 100 mmol) is added, then the reaction is heated undernitrogen to reflux. The reaction is monitored by TLC and HPLC butcomplete consumption of the starting material is never observed, andthen allowed to cool. The cooled reaction is concentrated and dilutedwith 250 mL ethyl acetate. The residue is washed with 100 mL saturatedsodium bicarbonate followed by water and brine. The organic layer isdried over anhydrous sodium sulfate, then concentrated and purified bycolumn chromatrography. The fractions that contained pure product areconcentrated to yield[5-Ethyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-acetic acid ethylester (4.0 g, 12.22 mmol) or 50% yield.

Step C

[5-Ethyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-acetic acid ethylester (4.0 g, 12.22 mmol) in anhydrous tetrahydrofuran (100 mL) iscooled to 0° C. and a 1M LiAlH₄ (12.2 mL, 12.2 mmol) solution is addedslowly. The reaction is monitored by TLC until complete consumption ofthe starting material. The reaction is then carefully quenched with 2.4mL water, 2.4 mL 5N NaOH and 7 mL water. The light tan solid is filterthrough celite and dried to give crude2-[5-Ethyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-ethanol (2.74 g,9.60 mmol) or 79% yield.

Step D

To a solution of2-[5-Ethyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-ethanol 2.74 g,9.60 mmol) in anhydrous dichloromethane (50 mL) is added dimethylaminopyridine (0.500 g, 4.00 mmol), tosic anhydride (8.4 g, 24 mmol), andpyridine (3.4 mL, 42 mmol) at room temperature. The reaction ismonitored by TLC, and upon complete consumption of the starting alcohol,the reaction is diluted with DCM and extracted against saturated sodiumbicarbonate solution. The organic layer is washed with water and brine,then dried over anhydrous sodium sulfate and concentrated. The puretoluene-4-sulfonic acid2-[5-ethyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-ethyl ester (3.0 g,6.82 mmol) is obtained after flash column chromatography.

Preparation 60 Toluene-4-sulfonic acid2-methyl-2-[5-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-propylester

Preparation 61 Toluene-4-sulfonic acid2-methyl-2-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-propylester

Preparation 621-[5-Ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-propan-2-ol

Step A

To a solution of2-[5-Ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-ethanol (1.25 g,4.16 mmol) in anhydrous dichloromethane (25 mL) at 0° C. under nitrogenis slowly added Dess-Martin periodinane (2.6 g, 6.24 mmol). The reactionis allowed to warm slowly to room temperature and monitored by TLC.After complete consumption of the starting material, the reaction isdiluted with dichloromethane and the two phases are seperated. Theorganic layer is washed, dried, filtered and concentrated. The crude[5-Ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-acetaldehyde (0.253g, 0.840 mmol), 21% yield, is further purified using flash columnchromatography.

Step B

[5-Ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-acetaldehyde (0.253g, 0.840 mmol), is dissolved in anhydrous tetrahydrofuran (5 mL) andcooled to 0° C. with stirring under nitrogen. Methylmagnesium bromide,3.0M in ether, (0.300 mL, 1.00 mmol) is added and the ice bath removed.After slowly warming to room temperature, the reaction is monitored byTLC. After the starting material is completely consumed, the reaction isquenched with saturated ammonium chloride solution and diluted withether. The two phases are separated and the organic washed with waterand brine, dried over sodium sulfate, then concentrated. The residue isfurther purified using flash column chromatography. The1-[5-Ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-propan-2-ol (0.222g, 0.7049 mmol) is formed in 70% yield.

Preparation 63C-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-methylamine

4-Azidomethyl-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole

To a solution of4-chloromethyl-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole (2.4 g,8.71 mmol) in methanol (13 mL) is added sodium azide (1.13 g, 17.4 mmol)in water (10 mL). The mixture is heated to reflux for 3 hrs, cooled toroom temperature, majority of the methanol is evaporated, the residue isextracted with ethyl acetate, dried, concentrated and colunchromatography on silica gel gave the title compound (2.10 g).

Step B C-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-methylamine

A mixture of 4-azidomethyl-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole(1.70 g) and PtO2 (0.106 g) in ethyl acetate (50 mL) at room temperatureunder 60 psi of hydrogen for 5 hrs, the reaction mixture is filteredthrough celite and filtrate is concentrated giving the title compound(1.3 g, 84.2% yield).

Preparation 642R-[5-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-propan-1-ol

The racemic alcohol2-[5-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-propan-1-ol isresolved on a Chiralpak AD column (4.6×250 mm). Eluted with ethanol inheptane and concentrated the fractions to provide pure enantiomers.

Preparation 652S-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-propan-1-ol

This compound is obtained in preparation 64.

Preparation 66 2-(4-Hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid

Step A 2-(4-Benzyloxy-2-formylphenoxy)-2-methyl propionic acid ethylester

5-Benzyloxy-2-hydroxy-benzaldehyde (Kappe, T.; Witoszynskyj, T. Arch.Pharm., 1975, 308 (5), 339–346) (2.28 g, 10.0 mmol), ethylbromoisobutyrate (2.2 mL, 15 mmol), and cesium carbonate (3.26 g, 10.0mmol) in dry DMF (25 mL) are heated at 80° C. for 18 h. The reactionmixture is cooled and partitioned between water (30 mL) and ether (75mL). The organic layer is washed with brine (15 mL). The aqueous layersare back-extracted with ethyl acetate (30 mL), and the organic layer iswashed with brine (20 mL). The combined organic layers are dried(Na₂SO₄) and concentrated to a brown oil. The crude product is purifiedby flash chromatography using hexanes:ethyl acetate (2.5:1) to give apale yellow solid (3.04 g, 89%): mp 65° C.; ¹H NMR (400 MHz, CDCl₃) δ1.24 (t, 3H, J=7.1 Hz), 1.62 (s, 6H), 4.23 (q, 2H, J=7.1 Hz), 6.81 (d,1H, J=8.8 Hz), 7.10 (dd, 1H, J=4.6, 9.0 Hz), 7.30–7.43 (m, 6H); MS (ES)m/e 343.1 [M+1].

Step B 2-(4-Hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethylester

2-(4-Benzyloxy-2-formyl-phenoxy)-2-methyl-propionic acid ethyl ester(9.00 g, 26.3 mmol) in ethanol (250 mL) is treated with 5% Pd/C (1.25 g)and hydrogen (60 psi, rt, overnight). Additional 5% Pd/C (1.25 g) isadded, and the reaction is continued for 6 h at 40° C. The mixture isfiltered and concentrated to a tan oil (6.25 g). This oil contained 9mol % of 2-(4-Hydroxy-2-hydroxymethyl-phenoxy)-2-methyl-propionic acidethyl ester. ¹H NMR (400 MHz, CDCl) δ 1.26 (t, 3H, J=7.3 Hz), 1.51 (s,6H), 2.14 (s, 3H), 4.24 (q, 2H, J=7.3 Hz), 5.68 (brs, 1H), 6.47 (dd, 1H,J=3.4, 8.8 Hz), 6.59 (d, 1H, J=8.3 Hz), 6.60 (brs, 1H).

The following compound is prepared in a similar manner:

Preparation 67 2-(4-Hydroxy-2-methyl-phenoxy)-acetic acid

¹H NMR (400 MHz, CDCl3) δ 1.28 (t, 3H, J=7.1 Hz), 2.24 (s, 3H), 4.25 (q,2H, J=7.1 Hz), 4.55 (s, 2H), 6.56 (dd, 1H, J=2.7, 8.5 Hz), 6.61 (d, 1H,J=8.3 Hz), 6.65 (d, 2H, J=2.9 Hz).

Preparation 68 (4-Hydroxy-2-propyl-phenoxy)-acetic acid ethyl ester

Step A 4-Benzyloxy-2-propylphenol

2-Allyl-4-benzyloxyphenol (WO 9728137 A1 19970807, Adams, A. D. et al.)(5.00 g, 20.8 mmol) in ethyl acetate (40 mL) is treated with 5% Pd/C(0.25 g) and hydrogen (1 atm) at ambient temperature for 18 h. Themixture is filtered and concentrated. The crude product is purified on aBiotage medium pressure chromatography system using a 40 L normal phasecartridge and eluted with 10% ethyl acetate in hexanes to give a tansolid (2.8 g, 56%). Rf=0.33 (25% EtOAc/Hexanes); ¹H NMR (400 MHz, CDCl₃)δ 7.44–7.31 (m, 5H), 6.78 (s, 1H), 6.69 (d, J=1.5 Hz, 2H), 5.00 (s, 2H),4.31 (s, 1H), 2.55 (t, J=7.6 Hz, 2H), 1.64 (q, J=7.5 Hz, 2H), 0.97 (t,J=7.3 Hz, 3H).

Step B (4-Benzyloxy-2-propylphenoxy)acetic acid ethyl ester

A solution of 4-benzyloxy-2-propylphenol (0.50 g, 1.94 mmol) in dry DMF(7 mL) is cooled in an ice bath and treated with NaH (0.15 g, 3.8 mmol,60% oil dispersion). The ice bath is removed, ethyl bromoacetate (0.43mL, 3.9 mmol) is added, and the mixture is placed in an oil bath (T=85°C.). After 18 h, the reaction mixture is cooled and concentrated invacuo. The residue is diluted with EtOAc, washed with brine (2×), dried(Na₂SO₄), and concentrated. The crude product is purified by radialchromatography using 10% ethyl acetate in hexanes to give a tan solid(0.62 g, 97%). ¹H NMR (400 MHz, CDCl₃) δ 7.44–7.31 (m, 5H), 6.82 (d,J=2.9 Hz, 1H), 6.72 (dd, J=8.8, 2.9 Hz, 1H), 6.66 (d, J=8.8 Hz, 1H),5.00 (s, 2H), 4.57 (s, 2H), 4.25 (q, J=7.0 Hz, 2H), 2.63 (t, J=7.6 Hz,2H), 1.64 (q, J=7.5 Hz, 2H), 1.29 (t, J=7.1 Hz, 3H), 0.95 (t, J=7.3 Hz,3H); MS (FIA) m/e 329 (M+1).

Step C (4-Hydroxy-2-propylphenoxy)acetic acid ethyl ester

A solution of (4-benzyloxy-2-propylphenoxy)acetic acid ethyl ester (0.60g, 1.83 mmol) in THF (15 mL) is treated with 5% Pd/C (75 mg) andhydrogen (60 psi) at ambient temperature for 24 h. The mixture isfiltered and concentrated. The crude product is purified by radialchromatography using 15% ethyl acetate in hexanes to give a tan solid(0.25 g, 57%). ¹H NMR (400 MHz, CDCl₃) δ 6.66 (d, J=2.9 Hz, 1H), 6.62(d, J=8.8 Hz, 1H), 6.57 (dd, J=8.8, 2.9 Hz, 1H), 4.56 (s, 1H), 4.40 (s,1H), 4.25 (q, J=7.2 Hz, 2H), 2.61 (t, J=7.6 Hz, 2H), 1.63 (q, J=7.5 Hz,2H), 1.29 (t, J=7.1 Hz, 3H), 0.95 (t, J=7.3 Hz, 3H); MS (FIA) m/e 239(M+1).

Preparation 69 (4-Mercapto-phenoxy)-acetic acid ethyl ester

Step A (4-Chlorosulfonyl-phenoxy)-acetic acid ethyl ester

Phenoxy-acetic acid ethyl ester (9.1 mL) is added to chlorosulfonic acid(15 mL) at 0° C. dropwise. The reaction is stirred at 0° C. for 30 min,it is allowed to warm to room temperature. After 2 hrs, the reactionmixture is poured into ice, solid product is collected by filtration anddried under vacuum.

Step B (4-Mercapto-phenoxy)-acetic acid ethyl ester

To a mixture of (4-chlorosulfonyl-phenoxy)-acetic acid ethyl ester (0.98g, 3.5 mmol) and tin powder (2.1 g) in ehtanol (4.4 mL) is added HCl indioxane (1.0 M, 4.4 mL) under nitrogen. The mixture is heated to refluxfor 2 hrs, it is poured into ice and methylene chloride and filtered.The layers are separated and extracted with methylene chloride, driedand concentrated. The crude product is used for next step withoutpurification.

The following compounds are made in a similar manner:

Preparation 70 (4-Mercapto-2-methyl-phenoxy)-acetic acid ethyl ester

This compound can also be made by the following procedure: To a stirredsuspension of Zn powder (10 μm, 78.16 g, 1.2 mol) and dichlorodimethylsilane (154.30 g, 145.02 mL, 1.2 mol) in 500 mL of dichloroethane isadded a solution of (4-chlorosulfonyl-2-methyl-phenoxy)-acetic acidethyl ester (100 g, 0.34 mol) and 1,3-dimethylimidazolidin-2-one (116.98g, 112.05 mL, 1.02 mol) in 1 L of DCE. Addition is at a rate so as tomaintain the internal temperature at ˜52° C., cooling with chilled wateras necessary. After addition is complete, the mixture is heated at 75°C. for 1 hour. It is then cooled to room temperature, filtered andconcentrated iv. Add MTBE, washed twice with saturated LiCl solutionconcentrate iv again. Take up the residue in CH₃CN, ish with hexane (4×)and concentrate iv to yield a biphasic mixture. Let stand in aseparatory funnel and separate layers, keeping the bottom layer forproduct. Filtration through a plug of silica gel (1 Kg, 25%EtOAc/hexane) and subsequent concentration yielded 61 g (79%) of aclear, colorless oil.

NMR (DMSO-d₆) δ 7.1 (s, 1H), 7.05 (dd, 1H), 6.75 (d, 1H), 5.03 (s, 1H),4.75 (s, 2H), 4.15 (q, 2H), 2.15 (s, 3H), 1.2 (t, 3H).

Preparation 71 (4-Mercapto-2-propyl-phenoxy)-acetic acid ethyl ester

Preparation 72 3-(4-Mercapto-2-methyl-phenyl)-propionic acid methylester

Step A 3-(4-Dimethylthiocarbamoyloxy-2-methyl-phenyl)-propionic acidmethyl ester

3-(4-Hydroxy-2-methyl-phenyl)-propionic acid methyl ester (5.0 g, 25.75mmol) is dissolved into dry dioxane (100 mL) and combined with4-dimethylamino pyridine (0.500 g, 2.6 mmol), triethylamine (7.0 mL,51.5 mmol), and dimethylaminothiocarbomoyl chloride (4.5 g, 32.17 mmol).The reaction is heated to reflux under nitrogen. The reaction ismonitored by TLC until all of the phenol is consumed, 20 h. Aftercooling to room temperature, the reaction is diluted with ethyl acetate(200 mL). Water (75 mL) is added and the two layers are seperated. Theorganic layer is washed with brine (75 mL) then dried over anhydroussodium sulfate. The solvent is removed and the residue is dried undervacuum.

Step B 3-(4-Dimethylcarbamoylsulfanyl-2-methyl-phenyl)-propionic acidmethyl ester

3-(4-Dimethylthiocarbamoyloxy-2-methyl-phenyl)-propionic acid methylester, taken crude from the previous step, is diluted with 75 mL oftetradecane and heated to reflux under nitrogen. The reaction ismonitored by TLC until all the conversion is complete, 20 h. Thereaction is allowed to cool to room temperature, then the tetradecane isdecanted away from the resulting oil. The residue is rinsed severaltimes with hexanes. This oil is then purified using flash columnchromatography, yielding 5.01 g, or 69% (2 steps) of the product.

Step C 3-(4-Mercapto-2-methyl-phenyl)-propionic acid methyl ester

3-(4-Dimethylcarbamoylsulfanyl-2-methyl-phenyl)-propionic acid methylester (5.01 g, 17.8 mmol) is diluted with methanol (30 mL) and to thisis added sodium methoxide (1.7 mL of 4M in methanol, 7.23 mmol). Thereaction is heated to reflux under nitrogen and monitored by TLC. Aftercomplete conversion, 20 h., the reaction is allowed to cool to roomtemperature. The reaction is nuetralized with 1N HCl (7.23 mL) anddiluted with ethyl acetate (150 mL). The two phases are seperated andthe organic layer is washed with water (75 mL), then brine (75 mL). Theorganic layer is then dried over anhydrous sodium sulfate, thenconcentrated to yield 4.43 g crude product that is used without furtherpurification.

Preparation 73 4-(2-Methoxycarbonyl-ethyl)-3-methyl-benzoic acid

Step A 4-Bromo-3-methyl-benzoic acid benzyl ester

To a solution of 4-Bromo-3-methyl-benzoic acid benzyl (25.3 g, 0.118mol) in DMF (200 mL) is added Cs2CO3 (76.6 g, 0.235 mol), followed bybenzyl bromide (15.4 mL). After stirred at room temperature for 2 h, thereaction mixture is diluted with ethyl acetate, filtered through celite.The filtrate is washed with water and brine, dried over sodium sulfate,concentration gave the title product.

Step B 4-(2-Methoxycarbonyl-vinyl)-3-methyl-benzoic acid benzyl ester

To a solution of 4-bromo-3-methyl-benzoic acid benzyl ester (36 g, 118mmol) in propronitrile (1000 mL) is added methyl acrylate (43.3 mL) anddiisopropylethyl amine (42 mL), the solution is degassed and filled withnitrogen for three times. To this mixture are addedtri-o-tolyl-phosphane (14.5 g) and palladium acetate (5.34 g) undernitrogen, then heated at 110° C. overnight, cooled to room temperature,filtered through celite. The solvent is evaporated, the residue is takeninto ethyl acetate and washed with water and brine, dried over sodiumsulfate. Concentration and column chromatography on silica gel elutedwith hexanes and ethyl acetate gave the title compound (31 g, 84.7%).

Step C 4-(2-Methoxycarbonyl-ethyl)-3-methyl-benzoic acid

A mixture of 4-(2-methoxycarbonyl-vinyl)-3-methyl-benzoic acid benzylester (11.6 g, 37.4 mmol) and Pd/C (5%, 1.5 g) in THF (300 mL) andmethanol (100 mL) is stirred under 60 psi of hydrogen overnight.Catalyst is filtered off, filtrate is concentrated giving the titlecompound (8.3 g, 100%).

Preparation 74 (4-Hydroxy-2-methyl-phenyl)-acetic acid methyl ester

Step A

4-Methoxy-2-methylbenzoic acid (2.5 g, 15.04 mmol) is stirred in thionylchloride (50 mL) at reflux 2 hr. The mixture is concentrated and dilutedwith toluene (10 mL) and concentrated. The resulting solid is driedunder vacuum 18 hr. The resulting acid chloride is stirred in 20 mLether at 0 deg C. A solution of diazomethane (39.6 mmol) in ether (150mL) is added to the acid chloride solution and stirred 18 hr. Theresulting diazoketone solution is concentrated. The residue is stirredin methanol (100 mL) and a solution of silver benzoate in triethylamine(1.0 g in 10 mL) is added and the reaction is heated to 60 deg C. andstirred 1 hr. The mixture is concentrated, diluted with 1.0 N aqueoushydrochloric acid (20 mL), extracted to three portions of ethyl acetate(50 mL each). The extracts are combined, washed with aqueous saturatedsodium hydrogen carbonate, water, and brine (50 mL each), dried overanhydrous magnesium sulfate, filtered and concentrated. The residue ispurified via silica gel chromatography eluting with 9:1 hexanes:ethylacetate to afford 1.5 g (51%) of the homologated ester as a white solid.

Step B

(4-Methoxy-2-methyl-phenyl)-acetic acid methyl ester (1.5 g, 7.72 mmol)is stirred in dichloromethane (50 mL) at 0 deg. C. Aluminum chloride(4.13 g, 31 mmol) is added followed by ethane thiol (2.9 mL, 38.6 mmol).The resulting mixture is stirred at room temperature for 2 hr. Water (50mL) is added and the product is extracted into ethyl acetate (3×50 ml),the extracts are combined, dried over anhydrous magnesium sulfate,filtered, and concentrated to afford the title compound as a colorlessoil, 1.4 g, 100%. MS M⁺+1 181. The structure is confirmed by ¹H NMRspectroscopy.

Preparation 75 (3-Hydroxy-phenyl)-acetic acid methyl ester

Step A (3-Hydroxy-phenyl)-acetic acid methyl ester

(3-Hydroxy-phenyl)-acetic acid (5.0 g, 32.86 mmol) is stirred inmethanol (100 mL) and concentrated (98%) sulfuric acid (3.0 mL.,) isadded. The mixture is heated to reflux 18 hr. The reaction is cooled andconcentrated. The residue is diluted with water (100 mL) and extractedwith ethyl acetate (3×50 mL). The combined extracts are dried overanhydrous magnesium sulfate, filtered, and concentrated to yield thetitle compound as an orange oil, 5.46 g, 100%. MS M⁺+1 167. Thestructure is confirmed by ¹H NMR spectroscopy.

The following compounds are made in a similar manner:

Preparation 76 (3-Hydroxy-4-methoxy-phenyl)-acetic acid methyl ester

An orange oil. MS M⁺+1 197. The structure is confirmed by ¹H NMRspectroscopy.

Preparation 77 3-(3-Hydroxy-phenyl)-propionic acid methyl ester

Step A 3-(3-Hydroxy-phenyl)-propionic acid methyl ester

An orange oil. MS M⁺+1 181. The structure is confirmed by ¹H NMRspectroscopy.

Preparation 78 (3-Mercapto-phenyl)-acetic acid methyl ester

Step A (3-Dimethylthiocarbamoyloxy-phenyl)-acetic acid methyl ester

A mixture of (3-Hydroxy-phenyl)-acetic acid methyl ester (5.5 g, 33.1mmol), N,N-dimethyl thiocarbamoyl chloride (5.11 g, 41.38 mmol),triethylamine (9.2 mL, 66.2 mmol), N,N-dimethylamino pyridine (0.4 g,3.31 mmol) and dioxane (50 mL) is stirred at reflux 18 hr. The mixtureis concentrated, partioned between 1M aqueous hydrochloric acid (200 mL)and ethyl acetate (3×75 mL). The combined organic extracts are driedover anhydrous magnesium sulfate, filtered, concentrated, and purifiedvia silica chromatography eluting the product with dichloromethane toafford the title compound as a brown oil, 6.8 g, 81%. MS M⁺+1 254. Thestructure is confirmed by ¹H NMR spectroscopy.

Step B (3-Dimethylcarbamoylsulfanyl-phenyl)-acetic acid methyl ester

(3-Dimethylthiocarbamoyloxy-phenyl)-acetic acid methyl ester (6.8 g,26.84 mmol) is stirred in tetradecane (30 mL) at 255 deg C. for 8 hr.The mixture is cooled, the residue is purified by silica chromatographyeluting the product with hexanes to 1:1 hexanes:ethyl acetate to affordthe title compound as an orange oil, 4.9 g, 58%. MS M⁺+1 254. Thestructure is confirmed by ¹H NMR spectroscopy.

Step C (3-Mercapto-phenyl)-acetic acid methyl ester

A mixture of (3-dimethylcarbamoylsulfanyl-phenyl)-acetic acid methylester (2.0 g, 7.9 mmol), potassium hydroxide (1.4 g, 24 mmol) methanol(50 mL), and water (5 mL) is stirred at reflux 3 hr. The mixture isconcentrated, and product partitioned between 1M aqueous hydrochloricacid (50 mL) and ethyl acetate (3×75 mL). The combined extracts aredried over anhydrous magnesium sulfate, filtered and concentrated. Theresidue is taken up in methanol (50 mL), 2 mL concentrated sulfuric acidis added, and the mixture refluxed 3 hr. The mixture is concentrated,and the residue purified by silica chromatography eluting with 7:3hexanes:ethyl acetate to afford the title compound as a pale yellow oil,1.0 g, 69%. MS M⁺+1 183. The structure is confirmed by ¹H NMRspectroscopy.

Preparation 79 3-(4-Iodomethyl-2-methyl-phenyl)-propionic acid methylester

Step A 3-(4-Hydroxymethyl-2-methyl-phenyl)-acrylic acid methyl ester

A mixture of methyl-4-bromo-3-methylbenzoate (5.7 g, 24.88 mmol),lithium aluminum hydride (29 mL, 29 mmol, 1 M solution intetrahydrofuran) and tetrahydrofuran (100 mL) is stirred in ice/waterfor 1 hr. The reaction is quenched with aqueous hydrochloric acid (50mL, 1 M). The product is extracted into ethyl acetate (3×100 mL). Thecombined extracts are dried over anhydrous magnesium sulfate, filteredand concentrated. The crude product is taken up in propionitrile (100mL). Methylacrylate (10 mL, 121.5 mmol), palladium acetate (1.12 g, 5mmol), tri-o-tolylphosphine (3.0 g, 10 mmol), and N,N-diisopropylethylamine (8.7 mL, 50 mmol) are sequentially added and the resultingreaction mixture is heated to 110 deg C. 3 hr. The mixture isconcentrated, and the residue diluted with aqueous hydrochloric acid(100 mL, 1M). The product is extracted with dichloromethane (2×100 mL)and ethyl acetate (100 mL). The combined extracts are dried overanhydrous magnesium sulfate, filtered, concentrated, and purified viasilica chromatography eluting with 7:3 hexanes:ethyl acetate to 1:1hexanes:ethyl acetate to afford the pure product as a yellow oil, 4.7 g,91%. MS M⁺+1 207. The structure is confirmed by ¹H NMR spectroscopy.

Step B 3-(4-Hydroxymethyl-2-methyl-phenyl)-propionic acid methyl ester

A mixture of 3-(4-Hydroxymethyl-2-methyl-phenyl)-acrylic acid methylester (4.7 g, 22.8 mmol), Raney nickel (0.668 g) and tetrahydrofuran(618 mL) is shaken under 60 psig. Hydrogen 24 hr. The catalyst isfiltered off, and the mixture is concentrated to afford the product as apale yellow oil, 4.3 g, 91%. The structure is confirmed by ¹H NMRspectroscopy.

Step C 3-(4-Iodomethyl-2-methyl-phenyl)-propionic acid methyl ester

A mixture of 3-(4-Hydroxymethyl-2-methyl-phenyl)-propionic acid methylester (0.62 g, 2.98 mmol), triphenyl phosphine (0.86 g, 3.27 mmol) anddichloromethane (10 mL) is stirred at room temperature. A solution ofiodine (0.83 g, 3.27 mmol) in benzene (5 mL) is added and the blackmixture is stirred at room temperature 2 hr. The brown mixture isdiluted with 10% aqueous sodium hydrogen sulfite (5 mL) and theresulting clear mixture is washed with ethyl acetate (3×50 mL). Thecombined extracts are dried over anhydrous magnesium sulfate, filteredand concentrated. The residue is purified via silica chromatographyeluting with 9:1 hexanes:ethyl acetate to afford the title compound as acrystalline ivory solid, 0.689, 72%. MS M⁺+1 319. The structure isconfirmed by ¹H NMR spectroscopy.

Preparation 80 (4-Bromo-2-methyl-phenoxy)-acetic acid methyl ester

Step A (4-Bromo-2-methyl-phenoxy)-acetic acid methyl ester

A mixture of 4-bromo-2-methylphenol (1.0 g, 5.35 mmol), sodium hydride(0.26 g, 6.42 mmol, 60% mineral oil), N,N-dimethylformamide (10 mL), andmethyl-2-bromoacetate (0.56 mL, 5.88 mmol) is stirred at roomtemperature 18 hr. The mixture is diluted with water (50 mL) and theproduct extracted to ethyl acetate (3×50 mL). The combined extracts aredried over anhydrous magnesium sulfate, filtered, concentrated andpurified via silica chromatography eluting with 8:2 hexanes:ethylacetate to afford title compound as a colorless oil, 1.03 g, 74%. MS M⁺259. The structure is confirmed by ¹H NMR spectroscopy.

Preparation 81 3-(4-Amino-2-methyl-phenyl)-propionic acid methyl ester

Step A 3-(2-Methyl-4-nitro-phenyl)-acrylic acid methyl ester

To a solution of 2-bromo-5-nitrotoluene (3.11 g, 14.39 mmol) inpropionitrile (105 mL) is added DIPEA (5.1 mL, 29.28 mmol). The mixtureis degassed three times. Methyl acrylate (5.2 mL, 57.74 mmol) is addedand the mixture is degassed. Tri-o-tolylphosphine (1.77 g, 5.82 mmol)and Pd(OAc)₂ (0.64 g, 2.85 mmol) are added and the mixture is degassed afinal two times followed by heating at 110° C. for 4 h. Upon cooling,the mixture is passed through Celite and the filtrate is concentrated.The residue is partitioned between Et₂O and 1N HCl. The organics arewashed with saturated NaHCO₃ and brine, and dried with Na₂SO₄. The crudematerial is purified by flash chromatography to yield the title compound(2.90 g, 91%).

Step B 3-(4-Amino-2-methyl-phenyl)-propionic acid methyl ester

A mixture of 3-(2-Methyl-4-nitro-phenyl)-acrylic acid methyl ester (1.47g, 6.64 mmol) and 5% Pd/C (0.29 g) in MeOH (100 mL) is exposed to ahydrogen atmosphere (60 psi) for 12 h. The mixture is filtered throughCelite and purified by flash chromatography to yield the title compound(0.99 g, 77%).

Preparation 82 3-(2-Methyl-4-methylaminomethyl-phenyl)-propionic acidmethyl ester TFA salt

Step A 3-(4-Formyl-2-methyl-phenyl)-propionic acid methyl ester

A mixture of 3-(4-Hydroxymethyl-2-methyl-phenyl)-propionic acid methylester (0.49 g, 2.35 mmol) and MnO₂ (0.80 g, 9.20 mmol) in chloroform (5mL) is stirred at RT for 4 days. The mixture is filtered through Celite;the Celite is washed with copious amounts of EtOAc. The filtrate isconcentrated and purified by flash chromatography to yield the titlecompound (0.29 g, 60%).

Step B 3-(2-Methyl-4-methylaminomethyl-phenyl)-propionic acid methylester trifluoroacetic acid

To a mixture of 3-(4-Formyl-2-methyl-phenyl)-propionic acid methyl ester(0.27 g, 1.31 mmol) and methylamine (2M in THF, 0.60 mL, 1.20 mmol) inanhydrous CH₂Cl₂ (10 mL) is added 4 Å molecular sieves followed byacetic acid (0.090 mL, 1.57 mmol). The mixture is stirred at RT for 1.5h. Sodium triacetoxyborohydride (0.39 g, 1.85 mmol) is added, and themixture is stirred overnight. The reaction is quenched with saturatedNaHCO₃. The organics are washed with saturated NaHCO₃ and brine, anddried with MgSO₄. Upon concentration, the mixture is purified by reversephase chromatography to yield the title compound (0.12 g, 45%).

Preparation 83 3-(4-Aminomethyl-2-methyl-phenyl)-propionic acid methylester

Step A 3-(4-Chloromethyl-2-methyl-phenyl)-propionic acid methyl ester

To a 0° C. solution of 3-(4-Hydroxymethyl-2-methyl-phenyl)-propionicacid methyl ester (1.02 g, 4.90 mmol) in anhydrous CH₂Cl₂ (15 mL) isadded triethylamine (0.75 mL, 5.38 mmol) followed by thionyl chloride(0.40 mL, 5.48 mmol). The mixture is allowed to warm to RT overnight.Water is added, and the mixture is extracted with CH₂Cl₂. The organicsare dried with MgSO₄ and concentrated. The crude material is purified byflash chromatography to yield the title compound (1.01 g, 91%).

Step B 3-(4-Azidomethyl-2-methyl-phenyl)-propionic acid methyl ester

To a solution of 3-(4-Chloromethyl-2-methyl-phenyl)-propionic acidmethyl ester (0.52 g, 2.31 mmol) in DMF (7 mL) is added sodium azide(0.25 g, 3.84 mmol). The mixture is stirred overnight. Water is added,and the mixture is extracted with EtOAc. The organics are dried withNa₂SO₄ and concentrated to yield the title compound (0.49 g, 91%). Thematerial is used without further purification.

Step C 3-(4-Aminomethyl-2-methyl-phenyl)-propionic acid methyl ester

A mixture of 3-(4-Azidomethyl-2-methyl-phenyl)-propionic acid methylester (0.20 g, 0.86 mmol) and 5% Pd/C (32 mg) in EtOH (50 mL) is exposedto a hydrogen atmosphere (60 psi) at RT overnight. Upon filtering themixture through Celite, the filtrate is concentrated to yield the titlecompound (0.14 g, 78%). The material is used without furtherpurification.

Preparation 843-(4-{2-[2-(4-Bromo-phenyl)-5-methyl-oxazol-4-yl]-propoxy}-2-methylphenyl)propionicacid methyl ester

Step A [2-(4-Bromo-phenyl)-5-methyl-oxazol-4-yl]-acetic acid methylester

Aspartic acid methyl ester hydrochloride salt (15.2 g, 82 mmol) isdissolved in water (200 mL) and cooled to 0° C. in an ice water bath.Sodium carbonate (25.3 g, 239 mmol) is slowly added in several portionsand the mixture is allowed to stir at 0° C. for 30 minutes.4-Bromobenzoyl chloride (16.8 g, 77.4 mmol) is dissolved into acetone(20 mL) at room temperature and transferred to an additional funnel. Theaddition funnel is connected to the aspartic acid mixture and slowlyadded over a period of two hours. The reaction is allowed to continue at0° C. for two hours, then the ice bath is removed. Upon reaching roomtemperature, the reaction is complete. The reaction is diluted withdichloromethane and acidified with concentrated hydrochloric acid. Thetwo phases are separated and the organic layer is washed with water andbrine. The organic layer is then dried over anhydrous sodium sulfate,filtered, and concentrated. The white solid is used without furtherpurification, and the yield is quantitative.

2-(4-Bromo-benzoylamino)-succinic acid 4-methyl ester (25.5 g, 77.4mmol) is dissolved in ethyl acetate (200 mL) at room temperature andpyridine (37.2 mL, 387 mmol), acetic acid anhydride (39.1 mL, 348.3mmol), and 4-N,N-dimethylamino pyridine (2.0 g, 7.74 mmol) are added.The reaction is heated to 90° C. under nitrogen. The reaction ismonitored by HPLC and upon complete consumption of the startingmaterial, is allowed to cool to room temperature. The reaction isdiluted with additional ethyl acetate and the two phases are separated.The organic layer is washed a few times with 1N HCl, then saturatedsodium bicarbonate solution, and finally brine. The organic layer isthen dried over anhydrous sodium sulfate, filtered, and concentrated.The 3-(4-Bromo-benzoylamino)-4-oxo-pentanoic acid methyl ester is usedin the next step without further purification.

3-(4-Bromo-benzoylamino)-4-oxo-pentanoic acid methyl ester is dissolvedin acetic anhydride (75 mL) and concentrated sulfuric acid is added in500 uL portions five times over a four hour period. The reaction ismonitored by HPLC. The reaction is then heated to 40° C. until thestarting material is consumed. The reaction is then concentrated todryness and purified by column chromatography. This procedure yielded(11.6 g, 37.4 mmol) 48.3% of the desired oxazole.

Step B 2-[2-(4-Bromo-Phenyl)-5-methyl-oxazol-4-yl]-propionic acid methylester

[2-(4-Bromo-phenyl)-5-methyl-oxazol-4-yl]-acetic acid methyl ester (11.6g, 37.4 mmol) is dissolved in anhydrous tetrahydrofuran (150 mL) andallowed to stir under nitrogen. Lithium diisopropyl amide solution intetrahydrofuran (28 mL of 2M soln., 56.1 mmol) is slowly added to thesolution at room temperature. This is then heated to 50° C. for 6 hours.The solution is allowed to cool to room temperature and methyl iodide(7.0 mL, 112 mmol) is added in one portion. The mixture is allowed tostir under nitrogen at room temperature overnight. The solution isquenched with a saturated solution of ammonium chloride, diluted withethyl acetate, and then enough water added to dissolve the solids. Thetwo phases are separated and the organic layer is washed with water andbrine, dried over anhydrous sodium sulfate, filtered, and concentrated.The pure 2-[2-(4-Bromo-phenyl)-5-methyl-oxazol-4-yl]-propionic acidmethyl ester (5.57 g, 17.19 mmol) is isolated in 46% yield after columnchromatography. The racemic2-[2-(4-Bromo-phenyl)-5-methyl-oxazol-4-yl)-propionic acid methyl esteris resolved on a Chiralcel OJ column (4.6×250 mm). Eluted with 40%isopropanol in heptane with 0.2% dimethy-ethylamine at 1 mL per minutewith detection at 260 nM and concentrated the fractions to provide thepure enantiomer esters (isomer 1, 99.8% ee; isomer 2, 99.4% ee).

Step C 2-[2-(4-Bromo-phenyl)-5-methyl-oxazol-4-yl]-propan-1-ol

2-[2-(4-Bromo-phenyl)-5-methyl-oxazol-4-yl]-propionic acid methyl ester(1.59 g, 5.13 mmol) is dissolved in anhydrous tetrahydrofuran at roomtemperature. The atmosphere is replaced with nitrogen and the solutionis cooled to 0° C. in an ice water bath. Lithium aluminum hydridesolution (5.2 mL of 1M solution in THF, 5.2 mmol) is slowly added to thesolution, and the reaction is monitored by HPLC. Upon completeconversion, the reaction is quenched with a saturated solution ofRochelle's salt. The ice bath is removed and the mixture is warmed toroom temperature. The reaction is diluted with diethyl ether and waterto dissolve any solids. The two phases are separated and the organicphase is washed with water and brine, dried over anhydrous sodiumsulfate, filtered, and concentrated. The2-[2-(4-Bromo-phenyl)-5-methyl-oxazol-4-yl]-propan-1-ol (1.25 g, 4.22mmol) is used without further purification. 82% yield.

Step D3-(4-{2-[2-(4-Bromo-phenyl)-S-methyl-oxazol-4-yl]-propoxy}-2-methylphenyl)propionicacid methyl ester

A solution of 2-[2-(4-Bromo-phenyl)-5-methyl-oxazol-4-yl]-propan-1-ol(1.25 g, 4.22 mmol) in anhydrous toluene (20 mL) is degassed and filledwith nitrogen for three times, and cooled to 0° C. in an ice water bath.Tri-n-butylphosphine (1.50 mL, 6.0 mmol) is added to the reactionmixture under nitrogen at 0° C., followed by addition of of1,1′-(azodicarbonyl)-dipiperidine (1.5 g, 6.0 mmol), and3-(4-Hydroxy-2-methyl-phenyl)-propionic acid methyl ester (989 mg, 5.07mmol). The reaction mixture is allowed to warm to room temperature andstirred overnight, the mixture is loaded on silica gel column.Chromatography gave the title compound (592 mg, 1.25 mmol) in 31% yield.

Preparation 85 [2-(6-Chloro-pyridin-3-yl)-5-methyl-oxazol-4-yl]-aceticacid methyl ester

Step A

Aspartic acid methyl ester hydrochloride salt (57 g, 310 mmol) isdissolved in dichloromethane (500 mL) and cooled to 0° C. in an icewater bath. Triethylamine (75 mL, 444 mmol) is slowly added in severalportions and the mixture is allowed to stir at 0° C. Meanwhile,6-chloronicotinic acid (35 g, 222 mmol) is dissolved intodichloromethane (500 mL) with a drop of dimethylformamide and cooled to0° C. in an ice water bath. After one hour at 0° C. the ice bath isremoved and the solution allowed to warm to room temperature. Thesolvent is evaporated, the solution concentrated to about 100 mL, andthen transferred to an addition funnel. This solution is then slowlyadded to the amino acid solution over two hours at 0° C. After twohours, the ice bath is removed. Upon reaching room temperature, thereaction is complete. The reaction is acidified with concentratedhydrochloric acid. The two phases are separated and the organic layer iswashed with water and brine. The organic layer is then dried overanhydrous sodium sulfate, filtered, and concentrated. The white solid isused without further purification.

Step B

2-[(6-Chloro-pyridine-3-carbonyl)-amino]-succinic acid 4-methyl ester(222 mmol) is dissolved in ethyl acetate (300 mL) at room temperatureand pyridine (90 mL, 1.11 mol), acetic anhydride (94 mL, 1.0 mol), anddimethyl amino pyridine (3.5 g, 22.2 mmol) are added. The reaction isheated to 90° C. under nitrogen. The reaction is monitored by HPLC andupon complete consumption of the starting material, is allowed to coolto room temperature. The reaction is diluted with additional ethylacetate and the two phases are separated. The organic layer is washed afew times with 1N HCl, then saturated sodium bicarbonate solution, andfinally brine. The organic layer is then dried over anhydrous sodiumsulfate, filtered, and concentrated. The3-[(6-Chloro-pyridine-3-carbonyl)-amino]-4-oxo-pentanoic acid methylester is used in the next step without further purification.

Step C

3-[(6-Chloro-pyridine-3-carbonyl)-amino]-4-oxo-pentanoic acid methylester is dissolved in acetic anhydride (75 mL) and concentrated sulfuricacid is added in 500 uL portions five times over a four hour period. Thereaction is monitored by HPLC. The reaction is then heated to 40° C.until the starting material is consumed. The reaction is allowed toproceed at room temperature overnight. The reaction is then concentratedto dryness and purified by column chromatography. This procedure yielded(12.8 g, 48 mmol) 22% of the desired oxazole over four steps.

Preparation 86[5-Methyl-2-(6-phenylsulfanyl-pyridin-3-yl)-oxazol-4-yl]-acetic acidmethyl ester

[2-(6-Chloro-pyridin-3-yl)-5-methyl-oxazol-4-yl]-acetic acid methylester (4.8 g, 17.98 mmol) is dissolved in anhydrous dimethylformamide(100 mL) and allowed to stir under nitrogen. Benzenethiol (2.78 mL, 27mmol) is added by syringe, followed by anhydrous cesium carbonate (12.6g, 36 mmol). The mixture is allowed to stir under nitrogen 50° C. andmonitored by HPLC. After complete consumption of strating material, thesolution is quenched with 1N sodium hydroxide solution, diluted withethyl acetate, and then enough water added to dissolve the solids. Thetwo phases are separated and the organic layer is washed with water andbrine, dried over anhydrous sodium sulfate, filtered, and concentrated.The pure (5-Methyl-2-(6-phenylsulfanyl-pyridin-3-yl)-oxazol-4-yl]-aceticacid methyl ester (4.51 g, 13.2 mmol) is isolated in 74% yield aftercolumn chromatography.

The following compound is made in a similar manner:

Preparation 87[5-Methyl-2-(6-phenylsulfanyl-pyridin-3-yl)-oxazol-4-yl]-acetic acidmethyl ester

Preparation 88

2-[5-Methyl-2-(6-phenylsulfanyl-pyridin-3-yl)-oxazol-4-yl]-propionicacid methyl ester

[5-Methyl-2-(6-phenylsulfanyl-pyridin-3-yl)-oxazol-4-yl]-acetic acidmethyl ester (4.51 g, 13.25 mmol) is dissolved in anhydroustetrahydrofuran (200 mL) and allowed to stir under nitrogen. Lithiumdiisopropyl amide solution in tetrahydrofuran (6.63 mL of 2M soln.,13.25 mmol) is slowly added to the solution at room temperature. This isallowed to stir under nitrogen for 6 hours at room temperature.Hexamethylphosphor-amide (9.2 mL, 53 mmol) is added to the reactionfollowed by methyl iodide (1.74 mL, 26.5 mmol), added in one portion.The mixture is allowed to stir under nitrogen at room temperatureovernight. The solution is quenched with a saturated solution ofammonium chloride, diluted with ethyl acetate, and then enough wateradded to dissolve the solids. The two phases are separated and theorganic layer is washed with water and brine, dried over anhydroussodium sulfate, filtered, and concentrated. The pure2-[5-Methyl-2-(6-phenylsulfanyl-pyridin-3-yl)-oxazol-4-yl]-propionicacid methyl ester (1.6 g, 4.51 mmol) is isolated in 34% yield aftercolumn chromatography. The racemic2-[5-Methyl-2-(6-phenylsulfanyl-pyridin-3-yl)-oxazol-4-yl]-propionicacid methyl ester is resolved on a Chiralpak AD column (4.6×150 mm).Eluted with 15% 3A alcohol in heptane with 0.2% dimethy-ethylamine at0.6 mL per minute with detection at 260 nm and concentrated thefractions to provide the pure enantiomer esters (isomer 1, 98.9% ee;isomer 2, 96.4% ee).

Preparation 89

2-[5-Methyl-2-(4-phenylsulfanyl-phenyl)-oxazol-4-yl]-propan-1-ol

2-[5-Methyl-2-(6-phenylsulfanyl-pyridin-3-yl)-oxazol-4-yl]-propionicacid methyl ester (507 mg, 1.43 mmol) is dissolved in anhydroustetrahydrofuran (5 mL) at room temperature. The atmosphere is replacedwith nitrogen and the solution is cooled to 0° C. in an ice water bath.Lithium aluminum hydride solution (1.43 mL of 1M soln., 1.43 mmol) isslowly added to the solution, and the reaction is monitored by HPLC.Upon complete conversion, the reaction is quenched with a saturatedsolution of Rochelle's salt. The ice bath is removed and the mixture iswarmed to room temperature. The reaction is diluted with ethyl acetateand water to dissolve any solids. The two phases are separated and theorganic phase is washed with water and brine, dried over anhydroussodium sulfate, filtered, and concentrated. The2-[5-Methyl-2-(4-phenylsulfanyl-phenyl)-oxazol-4-yl]-propan-1-ol (457mg, 1.40 mmol) is used without further purification (98% yield).

The following compound is made in a similar manner:

Preparation 90[5-Methyl-2-(6-phenylsulfanyl-pyridin-3-yl)-oxazol-4-yl]-acetic acidmethyl ester

Example 1(4-{1-[4-[2-(2-Chloro-6-fluoro-phenyl)-ethyl]-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethylsulfanyl}-2-methyl-phenoxy)-aceticacid

Step A(4-{1-[4-[2-(2-Chloro-6-fluoro-phenyl)-ethyl]-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethylsulfanyl}-2-methyl-phenoxy)-acetic acid ethyl ester

A solution of (4-Mercapto-2-methyl-phenoxy)-acetic acid (158 mg, 0.7mmol) and1-[4-[2-(2-Chloro-6-fluoro-phenyl)-ethyl]-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethanol(200 mg, 0.465 mmol) in toluene (3.0 mL) is degassed and filled withnitrogen for 3 times. Tributylphosphine (0.174 mL, 0.7 mmol) is added tothe reaction mixture under nitrogen at 0° C., followed by addition of of1,1′-(azodicarbonyl)-dipiperidine (177 mg, 0.7 mmol). The reactionmixture is allowed to warm to room temperature and stirred overnight,the mixture is loaded on silica gel column. Chromatography gave thetitle compound (160 mg).

Step B(4-{1-[4-[2-(2-Chloro-6-fluoro-phenyl)-ethyl]-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethylsulfanyl}-2-methyl-phenoxy)-acetic acid

(4-{1-[4-[2-(2-Chloro-6-fluoro-phenyl)-ethyl]-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethylsulfanyl}-2-methyl-phenoxy)-acetic acid ethyl ester (30 mg) is taken into THF(0.5 mL and treated with LiOH (1.0 N, 0.5 mL for 2 hrs. The reactionmixture is acidified with 5 N HCl, extracted with ethyl ether, driedover sodium sulfate. Concentration gave the title compound. MS (ES):610.1 (M⁺+1, ³⁵Cl), 612.1 (M⁺+1, ³⁷Cl), the structure is also confirmedby proton NMR.

The following compounds are made in a similar manner:

Example 2(2-Methyl-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-2-phenyl-ethylsulfanyl}-phenoxy)-aceticacid

MS (ES): 544.2 (M⁺+1, the structure is also confirmed by proton NMR.

Example 33-(2-Methyl-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-2-phenyl-ethoxy}-phenyl)-propionicacid

MS (ES): 526.2 (M⁺+1), the structure is also confirmed by proton NMR.

Example 4(4-{1-[4-[2-(2-Chloro-6-fluoro-phenyl)-ethyl]-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-2-methyl-phenoxy)-aceticacid

MS (ES): 594.2 (M⁺+1, ³⁵Cl), 596.2 (M⁺+1, ³⁷Cl), the structure is alsoconfirmed by proton NMR.

Example 53-(4-{1-[4-[2-(2-Chloro-6-fluoro-phenyl)-ethyl]-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionicacid

MS (ES): 592.2 (M⁺+1, ³⁵Cl), 594.2 (M⁺+1, ³⁷ Cl) the structure is alsoconfirmed by proton NMR.

Example 6(2-Methyl-4-{1-[4-phenethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethylsulfanyl}-phenoxy)-aceticacid

MS (ES): 558.2 (M⁺+1), the structure is also confirmed by proton NMR.

Example 7(2-Methyl-4-{1-[4-phenethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-phenoxy)-aceticacid

MS (ES): 542.2 (M⁺+1), the structure is also confirmed by proton NMR.

Example 83-(2-Methyl-4-{1-[4-phenethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-phenyl)-propionicacid

MS (ES): 540.2 (M⁺+1), the structure is also confirmed by proton NMR.

Example 9(2-Methyl-4-{1-[4-phenyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethylsulfanyl}-phenoxy)-aceticacid

MS (ES): 530.2 (M⁺+1), the structure is also confirmed by proton NMR.

Example 103-(2-Methyl-4-{1-[4-phenyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-phenyl)-propionicacid

MS (ES): 512.2 (M⁺+1), the structure is also confirmed by proton NMR.

Example 11(4-{1-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethylsulfanyl}-2-methyl-phenoxy)-aceticacid

MS (ES): 496.7 (M⁺+1), the structure is also confirmed by proton NMR.

Example 12(4-{1-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-2-methyl-phenoxy)-aceticacid

MS (ES): 480.6 (M⁺+1), the structure is also confirmed by proton NMR.

Example 133-(4-{1-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionicacid

MS (ES): 478.6 (M⁺+1), the structure is also confirmed by proton NMR.

Example 143-(4-{1-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethylsulfanyl}-2-methyl-phenyl)-propionicacid

MS (ES) 494.7 (M⁺+1), the structure is also confirmed by proton NMR.

Example 15(2-Methyl-4-{1-[4-phenylsulfanylmethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethylsulfanyl}-phenoxy)-aceticacid

MS (ES): 576.8 (M⁺+1), the structure is also confirmed by proton NMR.

Example 16(4-{1-[4-(3,5-Bis-trifluoromethyl-phenoxymethyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethylsulfanyl}-2-methyl-phenoxy)-aceticacid

MS (ES) 696.7 (M⁺+1), the structure is also confirmed by proton NMR.

Example 17(4-{1-[4-(2-Chloro-6-fluoro-phenoxymethyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethylsulfanyl}-2-methyl-phenoxy)-aceticacid

MS (ES): 613.2 (M⁺+1), the structure is also confirmed by proton NMR.

Example 183-(4-{1-[4-(3,5-Bis-trifluoromethyl-phenoxymethyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionicacid

MS (ES): 678.7 (M⁺+1), the structure is also confirmed by proton NMR.

Example 193-(4-{1-[4-(2-Chloro-6-fluoro-phenoxymethyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionicacid

MS (ES): 595.1 (M⁺+1), the structure is also confirmed by proton NMR.

Example 203-(2-Methyl-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-phenyl)-propionicacid

MS (ES): 450.6 (M⁺+1), the structure is also confirmed by proton NMR.

Example 213-(2-Methyl-4-{2-[5-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-propoxy}-phenyl)-propionicacid

MS (ES): 464.6 (M⁺+1), the structure is also confirmed by proton NMR.

Example 223-(2-Methyl-4-{2-methyl-2-[5-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-propoxy}-phenyl)-propionicacid

MS (ES): 478.6 (M⁺+1), the structure is also confirmed by proton NMR.

Example 233-(2-Methyl-4-{2-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-propoxy}-phenyl)-propionicacid

MS (ES): 448.5 (M⁺+1), the structure is also confirmed by proton NMR.

Example 24(S)-3-(2-Methyl-4-{2-[5-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-propoxy}-phenyl)-propionicacid

This compound is made in a similar manner using the chiral alcohol asstarting material. MS (ES): 480.7 (M⁺+1), the structure is alsoconfirmed by proton NMR.

Example 25(R)-3-(2-Methyl-4-{2-[5-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-propylsulfanyl}-phenyl)-propionicacid

This compound is made in a similar manner using the chiral alcohol asstarting material. MS (ES): 480.7 (M⁺+1), the structure is alsoconfirmed by proton NMR.

Example 26(4-{1R-[4-[2-(2-Chloro-6-fluoro-phenyl)-ethyl]-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethylsulfanyl}-2-methyl-phenoxy)-aceticacid

The racemic ethyl ester of4-{1R-[4-[2-(2-Chloro-6-fluoro-phenyl)-ethyl]-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethylsulfanyl}-2-methyl-phenoxy)-aceticacid is resolved on a Chiralcel OD column (2.1×25 cm). Eluted withethanol in heptane and concentrated the fractions to provide a pureenantiomer ester (isomer 1, 100% ee). Hydrolysis of the pure enantiomerof the ester provided the title compound as a white solid.

The following enantiomeric pure compounds are obtained by similar chiralseparation using Chiralcel OD column (2.1×25 cm) or using Chiralcel OJcolumn (2.1×25 cm):

Example 27(4-{1S-[4-[2-(2-Chloro-6-fluoro-phenyl)-ethyl]-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethylsulfanyl}-2-methyl-phenoxy)-aceticacid

Example 28(2-Methyl-4-{1S-[4-phenethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-phenoxy)-aceticacid

Example 29(2-Methyl-4-{1R-[4-phenethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-phenoxy)-aceticacid

Example 30(2-Methyl-4-{1S-[4-phenethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethylsulfanyl}-phenoxy)-aceticacid

Example 31(2-Methyl-4-{1R-[4-phenethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethylsulfanyl}-phenoxy)-aceticacid

Example 32(R)-(4-{1-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethylsulfanyl}-2-methyl-phenoxy)-aceticacid

MS (ES): 496.7 (M⁺+1), the structure is also confirmed by proton NMR.

Example 33(S)-(4-{1-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethylsulfanyl}-2-methyl-phenoxy)-aceticacid

MS (ES): 496.7 (M⁺+1), the structure is also confirmed by proton NMR.

Example 34(S)-(4-{1-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-2-methyl-phenoxy)-aceticacid

MS (ES): 480.6 (M⁺+1), the structure is also confirmed by proton NMR.

Example 35(R)-(4-{1-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-2-methyl-phenoxy)-aceticacid

MS (ES): 480.6 (M⁺+1), the structure is also confirmed by proton NMR.

Example 36(S)-3-(4-{1-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionicacid

MS (ES): 478.6 (M⁺+1), the structure is also confirmed by proton NMR.

Example 37(R)-3-(4-{1-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionicacid

MS (ES): 478.6 (M⁺+1), the structure is also confirmed by proton NMR.

Example 38(R)-3-(4-{1-[4-(2-Chloro-6-fluoro-phenoxymethyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionicacid

MS (ES): 595.1 (M⁺+1), the structure is also confirmed by proton NMR.

Example 39(S)-3-(4-{1-[4-(2-Chloro-6-fluoro-phenoxymethyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionicacid

MS (ES): 595.1 (M⁺+1), the structure is also confirmed by proton NMR.

Example 40(R)-(4-{1-[4-(2-chloro-6-fluoro-phenoxymethyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethylsulfanyl}-2-methyl-phenoxy)-aceticacid

MS (ES): 612.1 (M⁺+1), the structure is also confirmed by proton NMR.

Example 41(S)-(4-{1-[4-(2-Chloro-6-fluoro-phenoxymethyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethylsulfanyl}-2-methyl-phenoxy)-aceticacid

MS (ES): 612.1 (M⁺+1), the structure is also confirmed by proton NMR.

Example 42(S)-(2-Methyl-4-{1-[4-phenylsulfanylmethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethylsulfanyl}-phenoxy)-aceticacid

MS (ES): 576.07 (M⁺+1), the structure is also confirmed by proton NMR.

Example 43(R)-(2-Methyl-4-{1-[4-phenylsulfanylmethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethylsulfanyl}-phenoxy)-aceticacid

MS (ES): 576.07 (M⁺+1), the structure is also confirmed by proton NMR.

Example 44(R)-3-(2-Methyl-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-phenyl)-propionicacid

MS (ES): 450.6 (M⁺+1), the structure is also confirmed by proton NMR.

Example 45(S)-3-(2-Methyl-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-phenyl)-propionicacid

MS (ES): 450.6 (M⁺+1), the structure is also confirmed by proton NMR.

Example 46(S)-3-(2-Methyl-4-{2-[5-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-propoxy}-phenyl)-propionicacid

MS (ES): 464.2 (M⁺+1), the structure is also confirmed by proton NMR.

Example 47(R)-3-(2-Methyl-4-{2-[5-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-propoxy}-phenyl)-propionicacid

MS (ES) 464.2 (M⁺+1) the structure is also confirmed by proton NMR.

Example 483-(4-{1-[4-Ethyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionicacid

Step A3-(4-{1-[4-Ethyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionicacid methyl ester

To a solution of1-[4-ethyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethanol (0.114 g,0.400 mmole) and 3-(4-Hydroxy-2-methyl-phenyl)-propionic acid methylester (0.0789, 0.400 mmole) in toluene (2 mL) at room temperature, isadded tributylphosphine (0.200 mL, 0.800 mmole) followed by a solutionof 1,1′-(azodicarbonyl)-dipiperidine (0.201 g, 0.800 mmole) in toluene(2 mL). The reaction is stirred overnight, then diluted with hexane (10mL). The precipitate is removed through filtration and the filtrate isconcentrated, loaded to a silica gel column, eluted with ethyl acetatein hexane (0–15%) and concentrated to provide the titled compound as awhite solid. Mass [EI+] 462 (M+H)⁺.

Step B3-(4-{1-[4-Ethyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionicacid

3-(4-{1-[4-Ethyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionicacid methyl ester (0.095 g, 0.206 mmole) is treated with a mixture ofNaOH_((aq)) (1 mL)/THF (3 mL)/MeOH (3 mL) at room temperature overnight.The organic solvents are removed on rota-vapor. The residue is dilutedwith water (10 mL), acidified to pH=2 with 6N HCl_((aq)). Theprecipitate is collected through filtration, washed with cold water (30mL) and dried to provide the titled compound as a white solid. Mass[EI+] 448 (M⁺+H), 446 (M⁺−H).

The following Compounds are made in this manner.

Example 49(4-{1-[4-Ethyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethoxy}-2-methyl-phenoxy)-aceticacid

White solid. Mass [EI+] 450 (M⁺+H), 448 (M⁺−H).

Example 50(4-{1-[4-Ethyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethylsulfanyl}-2-methyl-phenoxy)-aceticacid

White solid. Mass [EI+] 466 (M⁺+H), 464 (M⁺−H).

Example 51(4-{1R-[4-Ethyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethylsulfanyl}-2-methyl-phenoxy)-aceticacid

The racemic methyl ester of(4-{1-[4-ethyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethylsulfanyl}-2-methyl-phenoxy)-aceticacid is resolved on a Chiralcel OJ column (2.1×25 cm). Eluted with 40%ethanol in heptane and concentrated the fractions to provide a pureenantiomer ester (isomer 1, 100% ee). Hydrolysis of the pure enantiomerof the ester provides the titled compound as a white solid. Mass [EI+]466 (M⁺+H), 464 (M⁺−H).

Example 52(4-{1S-[4-Ethyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethylsulfanyl}-2-methyl-phenoxy)-aceticacid

From the chiral separation in previous example also gave the ester ofthis enantiomer. Hydrolysis of the pure enantiomer of the ester providesthe titled compound as a white solid. Mass [EI+] 466 (M+H)⁺, 464 (M+H)⁻.

Example 533-(2-Methyl-4-{1S-[4-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-2-phenyl-ethoxy}-phenyl)-propionicacid

To a solution of1-[4-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-2-phenyl-ethanone(1.2 g, 3.5 mmol) in 50 mL MeOH at 0° C. is added LiBH₄ (0.086 g, 3.50mmol) portionwise. After gas evolution had ceased a tic indicated thatthe reaction is complete and 50 mL of NH₄Cl (aq.) is added and theresultant solution extraxted with ethyl acetate (3×50 mL). The combinedorganics are dried (Na₂SO₄), filtered and concentrated under vacuo. Theresultant crude oil is purified by flash column chromatography (10%–20%)ethyl acetate/hexane to provide 1.1 g1-[4-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-2-phenyl-ethanol.To a solution of1-[4-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-2-phenyl-ethanol(0.50 g, 1.44 mmol), 3-(4-Hydroxy-2-methyl-phenyl)-propionic acid methylester (0.28 g, 1.44 mmol) and 1,1′-(azodicarbonyl)-dipiperidine (0.54 g,2.16 mmol) in 15 mL toluene is added tributylphosphine (0.5 mL, 2.16mmol). After 1 hr the volatiles are removed and the crude ester purifiedby flash column chromatography (10%–25%) ethyl acetate/hexane to provide0.34 g (45%) of3-(2-Methyl-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-2-phenyl-ethoxy}-phenyl)-propionicacid methyl ester as the racemate. The ester is separated by HPLCutilizing a chiral column with ethanol as the eluent. Thisenatiomerically pure ester (0.097 g, 0.18 mmol) is hydrolyzed in theusual manner 3 eq. 1N LiOH in 0.5 mL 3:2:1 solution of THF:MeOH:H₂O toprovide 0.09 g (93%) of the title compound. MS (M⁺+1) 510.

Example 543-(2-Methyl-4-{1R-[4-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-2-phenyl-ethoxy}-phenyl)-propionicacid

3-(2-Methyl-4-{1R-[4-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-2-phenyl-ethoxy}-phenyl)-propionicacid ethyl ester (0.09 g, 0.17 mmol) obtained as described above ishydrolyzed in the usual manner 3 eq. 1N LiOH in 0.5 mL 3:2:1 solution ofTHF:MeOH:H₂O to provide 0.08 g (89%) of the title compound. MS (M⁺+1)510.

Example 553-(2-Methyl-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethoxy}-phenyl)-propionicacid

Step 13-(2-Methyl-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethoxy}-phenyl)-propionicacid methyl ester

1-[4-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethanol (0.15 g,0.553 mmol) and 3-(4-Hydroxy-2-methyl-phenyl)-propionic acid methylester (0.12 g, 0.610 mmol) are stirred in 10 mL toluene at 0° C. under anitrogen atmosphere. Tri-n-butylphosphine (0.21 mL, 0.83 mmol) is addedfollowed by 1,1′-(Azodicarbonyl)dipiperidine (0.21 g, 0.83 mmol). Themixture is allowed to stir at room temperature for 20 hr. The resultingslurry is concentrated under reduced pressure. 50 mL of a 1:1 solutionof ethyl acetate:hexanes is added, and the slurry is filtered. Theresulting solution is concentrated and purified by silica gelchromatography eluting with a mixture of 8:2 hexanes:ethyl acetateyielding3-(2-Methyl-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethoxy}-phenyl)-propionicacid methyl ester as a white solid, 0.176 g (71%). MS (M⁺+1) 446.

Step 23-(2-Methyl-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethoxy}-phenyl)-propionicacid

3-(2-Methyl-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethoxy}-phenyl)-propionicacid methyl ester (0.176 g, 0.393 mmol) is dissolved in 20 mL of a 3:2:1mixture of THF:MeOH:H₂O. Lithium hydroxide (0.050 g, 2.08 mmol) is addedand the resulting mixture is heated to 60° C. for 1 hr. The mixture iscooled to room temperature, diluted with 50 mL water and the pH isadjusted to 2–3 with 1M HCl. The product is extracted with two 50 mLportions of ethyl acetate. The combined organic extracts are washed with50 mL water, dried over anhydrous magnesium sulfate, filtered, andconcentrated to yield the title compound,3-(2-Methyl-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethoxy}-phenyl)-propionicacid as a white solid, 0.12 g (71%). MS (M⁺+1) 434.

The following compounds are made in a similar manner as Example 55:

Example 563-(2-Methyl-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-propoxy}-phenyl)-propionicacid

The structure is confirmed by MS. MS (M⁺−1) 448.

Example 573-(2-Methyl-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-but-3-enyloxy}-phenyl)-propionicacid

The structure is confirmed by MS. MS (M⁺+1) 460.

Example 583-(2-Methyl-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-pentyloxy}-phenyl)-propionicacid

The structure is confirmed by MS. MS (M⁺+1) 476.

Example 593-(4-{1-[4-tert-Butyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionicacid

The structure is confirmed by MS. MS (M⁺+1) 476.

Example 603-(4-{1-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethoxy}-2-methyl-Phenyl)-propionicacid

The structure is confirmed by MS. MS (M⁺+1) 462.

Example 613-(4-{2-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-propoxy}-2-methyl-phenyl)-propionicacid

The structure is confirmed by MS. MS (M⁺+1) 476.

Example 623-(2-Methyl-4-{2-methyl-2-[5-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-propylsulfanyl}-phenyl)-propionicacid

MS (ES): 494.07 (M⁺+1).

Example 63(R)-(3-{2-[5-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-propoxy}-phenyl)-aceticacid

MS (ES): 436.1 (M⁺+1).

Example 643-(2-Methyl-4-{2-methyl-2-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-propylsulfanyl}-phenyl)-propionicacid

MS (ES) 478.11 (M⁺+1).

Example 653-(4-{2-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propoxy}-2-methyl-phenyl)-propionicacid

Step 1

2-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propan-1-ol(329 mg, 1.0 mmol) is dissolved into anhydrous toluene (5 mL) and cooledin an ice bath to 0° C. with stirring under nitrogen. Tributyl phosphine(400 uL, 1.50 mmol) is added by syringe followed by1-1′-azodicarbonyl-dipiperidine (405 mg, 1.50 mmol). Finally,3-(4-Hydroxy-2-methyl-phenyl)-propionic acid methyl ester (200 mg, 1.20mmol) is then added. The reaction is allowed to stir under nitrogen at0° C. for 1 hour, then room temperature and monitored by TLC and HPLC.Upon completion, the reaction is diluted with hexanes and allowed tostir vigorously for 10 min. The resulting white precipitate is thenfiltered away and the solution is concentrated under vacuum. The residueis further purified using either EtOAc/Hexanes (1:9) or Acetone/Hexanes(1:9) gradients on silica gel chromatography to yield3-(4-{2-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propoxy}-2-methyl-phenyl)-propionicacid methyl ester (239 mg, 0.4725 mmol) or 45%.

Step 2

3-(4-{2-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propoxy}-2-methyl-phenyl)-propionicacid methyl ester (239 mg, 0.4725 mmol) is dissolved in tetrahydrofuran(1 mL) and 5N NaOH (1 mL) is added. The mixture is heated to refluxuntil the conversion is complete. Upon complete conversion, the reactionis cooled to room temperature and 5N HCl (1 mL) is added. The mixture isdiluted with diethyl ether and extracted with 1N HCl. The organic layeris washed with water and brine, then dried over anhydrous sodiumsulfate. Concentration of the solvent reveals the pure3-(4-{2-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propoxy}-2-methyl-phenyl)-propionicacid in near quantitative yield (221 mg, 0.4489 mmol).

The following compounds are made in a substantially similar manner:

Example 66Racemic-3-(2-Methyl-4-{2-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-propoxy}-phenyl)-propionicacid

MS (ES): 448.24 (M⁺+1).

Example 67(S)-3-(2-Methyl-4-{2-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-propoxy}-phenyl)-propionicacid

MS (ES): 448.15 (M⁺+1).

Example 68(R)-3-(2-Methyl-4-{2-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-propoxy}-phenyl)-propionicacid

MS (ES): 448.15 (M⁺+1).

Example 692-Methoxy-3-(4-{2-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-propoxy}-phenyl)-propionicacid

MS (ES): 464.1 (M⁺+1).

Example 70Racemic-(3-{2-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-propylsulfanyl}-phenyl)-aceticacid

MS (ES): 436.11 (M⁺+1).

Example 712-Methoxy-3-(4-{2-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-propoxy}-phenyl)-propionicacid

MS (ES): 464.13 (M⁺+1).

Example 722-Methoxy-3-(4-{2-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-propoxy}-phenyl)-propionicacid

MS (ES): 464.13 (M⁺+1).

Example 733-(4-{2-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propoxy}-2-methyl-phenyl)-propionicacid

MS (ES): 492.13 (M⁺+1).

Example 743-(4-{2-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propylsulfanyl}-2-methyl-phenyl)-propionicacid

MS (ES): 508.12 (M⁺+1).

Example 75(4-{2-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propylsulfanyl}-2-methyl-phenoxy)-aceticacid

MS (ES): 510.09 (M⁺+1).

Example 76(3-{2-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propoxy}-phenyl)-aceticacid

MS (ES): 464.13 (M⁺+1).

Example 77(R)-3-(4-{2-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propoxy}-2-methyl-phenyl)-propionicacid

MS (ES): 492.16 (M⁺+1).

Example 78(S)-3-(4-{2-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propoxy}-2-methyl-phenyl)-propionicacid

MS (ES): 492.13 (M⁺+1).

Example 783-(2-Methyl-4-{2-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propoxy}-phenyl)-propionicacid

MS (ES): 464.11 (M⁺+1).

Example 793-(2-Methyl-4-{2-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propylsulfanyl}-phenyl)-propionicacid

MS (ES): 480.1 (M⁺+1).

Example 80(3-{2-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propoxy}-phenyl)-aceticacid

MS (ES): 436.09 (M⁺+1).

Example 81(R)-(3-{2-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propoxy}-phenyl)-aceticacid

MS (ES): 464.08 (M⁺+1).

Example 82(R)-(3-{2-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propoxy}-phenyl)-aceticacid

MS (ES): 464.09 (M⁺+1).

Example 83(S)-(3-{2-[5-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-propoxy}-phenyl)-aceticacid

MS (ES): 434.07 (M⁺−1).

Example 84(R)-(3-{2-[5-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-propoxy}-phenyl)-aceticacid

MS (ES): 436.1 (M⁺+1).

Example 853-(4-{2-[5-Ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-propoxy}-2-methyl-phenyl)-propionicacid

MS (ES): 478.1 (M⁺+1).

Example 863-(4-{2-[5-Ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-propylsulfanyl}-2-methyl-phenyl)-propionicacid

MS (ES): 494.1 (M⁺+1).

Example 87(4-{2-[5-Ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-propylsulfanyl}-2-methyl-phenoxy)-aceticacid

MS (ES): 496.0 (M⁺+1).

Example 88(3-{2-[5-Ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-propoxy}-phenyl)-aceticacid

MS (ES): 450.11 (M⁺+1).

Example 89(S)-3-(4-{2-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propylsulfanyl}-2-methyl-phenyl)-propionicacid

MS (ES): 508.07 (M⁺+1).

Example 90(R)-3-(4-{2-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propylsulfanyl}-2-methyl-phenyl)-propionicacid

MS (ES): 508.07 (M⁺+1).

Example 91(R)-(4-{2-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propylsulfanyl}-2-methyl-phenoxy)-aceticacid

MS (ES): 510.08 (M⁺+1).

Example 92(R)-(4-{2-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propylsulfanyl}-2-methyl-phenoxy)-aceticacid

MS (ES): 510.09 (M⁺+1).

Example 93(3-{2-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propylsulfanyl}-phenyl)-aceticacid

MS (ES): 480.12 (M⁺+1).

Example 943-(4-{2-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propoxy}-phenyl)-2-methoxy-propionicacid

MS (ES): 506.15 (M⁺+1).

Example 952-(4-{2-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propoxy}-2-methyl-phenoxy)-2-methyl-propionicacid

MS (ES): 522.1 (M⁺+1).

Example 96

3-(4-{2-[4-Isopropyl-2-(4-trifluoromethoxy-phenyl)-oxazol-5-yl]-propoxy}-2-methyl-phenyl)-propionicacid Step A

A solution of2-[4-isopropyl-2-(4-trifluoromethoxy-phenyl)-oxazol-5-yl]-propan-1-ol(230 mg, 0.699 mmol) and 2,6-di-t-butyl-4-methylpyridine (229 mg, 1.12mmol) in CH₂Cl₂ (20 mL) at −40° C. is treated with triflic anhydride(0.165 mL, 0.979 mmol). The reaction mixture is stirred at −40° C. for20 minutes and then quenched with MeOH (0.2 mL). The mixture isimmediately concentrated to crude triflate and it is dissolved in THF (5mL) and cooled to 0° C. In the meantime, a solution of3-(4-hydroxy-2-methyl-phenyl)-propionic acid methyl ester (165 mg, 0.839mmol) in THF (5 mL) is treated with LiHMDS (0.84 mL, 1.0 M in THF) andstirred for 5 minutes. Cannula this phenoxide solution to the crudetriflate solution and the resulting mixture is stirred for 12 hourswhile warmed up to room temperature. The mixture is concentrated andpurified on silica gel chromatography with 10–15% EtOAc/Hexanes toafford the intermediate compound (239 mg, 68%).

Step B

A solution of3-(4-{2-[4-isopropyl-2-(4-trifluoromethoxy-phenyl)-oxazol-5-yl]-propoxy}-2-methyl-phenyl)-propionicacid methyl ester (239 mg, 0.473) in MeOH (1.0 mL) and THF (0.5 mL) istreated with NaOH (1.5 mL, 2.0 M) and stirred at room temperature for 12hours. The mixture is neutralized to pH=4 with HCl (5 N) and extractedwith EtOAc (20 mL×2), and the combined organics are dried (Na₂SO₄),concentrated and purified on silica gel chromatography column withEtOAc/Hexanes (50/50) to yield the acid as white solid (202 mg, 87%). MS(ES): 492.2; the structure is also confirmed by proton NMR.

Example 973-(4-{1-[4-Isopropyl-2-(4-trifluoromethoxy-phenyl)-oxazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionicacid

Step A3-(4-{1-[4-Isopropyl-2-(4-trifluoromethoxy-phenyl)-oxazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionicacid methyl ester

A solution of1-[4-isopropyl-2-(4-trifluoromethoxy-phenyl)-oxazol-5-yl]-ethanol (140mg, 0.446 mmol) and 3-(4-hydroxy-2-methyl-phenyl)-propionic acid methylester (122 mg, 0.624 mmol) in toluene (15 mL) is degassed and filledwith nitrogen for 3 times. Tributylphosphine (144 mg, 0.713 mmol) isadded to the reaction mixture under nitrogen at 0° C., followed byaddition of of 1,1′-(azodicarbonyl)-dipiperidine (169 mg, 0.669 mmol).The reaction mixture is allowed to warm to room temperature and stirredfor 4 hours. The mixture is loaded directly on silica gel columnchromatography with 10–25% EtOAc/Hexanes to afford the title compound(25 mg, 11%).

Step B3-(4-{1-[4-Isopropyl-2-(4-trifluoromethoxy-phenyl)-oxazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionicacid

A solution of3-(4-{1-[4-Isopropyl-2-(4-trifluoromethoxy-phenyl)-oxazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionicacid methyl ester in MeOH (1.0 mL) and THF (0.5 mL) is treated with NaOH(1.5 mL, 2.0 M) and stirred at room temperature for 2 hours. The mixtureis neutralized to pH=6 with HCl (5 N) and extracted with EtOAc (20mL×2), and the combined organics are dried (Na₂SO₄), concentrated andpurified on silica gel chromatography column with EtOAc/Hexanes (50/50)to yield the acid as white solid (14 mg). MS (ES): 478.2; the structureis also confirmed by proton NMR.

The following compounds are made in a similar manner:

Example 98(4-{1-[4-Isopropyl-2-(4-trifluoromethoxy-phenyl)-oxazol-5-yl]-ethylsulfanyl}-2-methyl-phenoxy)-aceticacid

MS (ES): 496.1; the structure is also confirmed by proton NMR.

Example 99(4-{1-[4-Isopropyl-2-(4-trifluoromethoxy-phenyl)-oxazol-5-yl]-ethoxy}-2-methyl-phenoxy)-aceticacid

MS (ES): 480.2; the structure is also confirmed by proton NMR.

Example 1003-(4-{2-[4-Isopropyl-2-(4-phenoxy-phenyl)-oxazol-5-yl]-propoxy}-2-methyl-phenyl)-propionicacid

A solution of 1-[4-isopropyl-2-(4-phenoxyphenyl)-oxazol-5-yl]-ethanol(160 mg, 0.474 mmol) and 3-(4-hydroxy-2-methyl-phenyl)-propionic acidmethyl ester (120 mg, 0.614 mmol) in toluene (10 mL) is degassed andfilled with nitrogen for 3 times. Tributylphosphine (153 mg, 0.759 mmol)is added to the reaction mixture under nitrogen at 0° C., followed byaddition of of 1,1′-(azodicarbonyl)-dipiperidine (167 mg, 0.614 mmol).The reaction mixture is allowed to warm to room temperature and stirredfor 2 hours. The mixture is loaded directly on silica gel columnchromatography with 10–25% EtOAc/Hexanes to afford the intermediatecompound.

The intermediate is then dissolved in MeOH (1.0 mL) and THF (0.5 mL) andis treated with NaOH (1.5 mL, 2.0 M) and stirred at room temperature for2 hours. The mixture is neutralized to pH=6 with HCl (5 N) and extractedwith EtOAc (20 mL×2), and the combined organics are dried (Na₂SO₄),concentrated to yield the acid as white solid (55 mg, 23%). MS (ES):500.2; the structure is also confirmed by proton NMR.

Example 1013-(4-{2-[2-(4-Bromo-phenyl)-4-isopropyl-oxazol-5-yl]-propoxy}-2-methyl-phenyl)-propionicacid methyl ester

A solution of 2-[2-(4-bromo-phenyl)-4-isopropyl-oxazol-5-yl]-propan-1-ol(225 mg, 0.694 mmol) and 3-(4-hydroxy-2-methyl-phenyl)-propionic acidmethyl ester (190 mg, 0.972 mmol) in toluene (15 mL) is degassed andfilled with nitrogen for 3 times. Tributylphosphine (224 mg, 1.11 mmol)is added to the reaction mixture under nitrogen at 0° C., followed byaddition of of 1,1′-(azodicarbonyl)-dipiperidine (280 mg, 1.11 mmol).The reaction mixture is allowed to warm to room temperature and stirredovernight, the mixture is loaded directly on silica gel columnchromatography with 10–15% EtOAc/Hexanes to afford the title compound(320 mg, 92%).

Example 1023-[4-(2-{4-Isopropyl-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-oxazol-5-yl}-propoxy)-2-methyl-phenyl]-propionicacid methyl ester

To a solution of3-(4-{2-[2-(4-Bromo-phenyl)-4-isopropyl-oxazol-5-yl]-propoxy}-2-methyl-phenyl)-propionicacid methyl ester (0.871 g, 1.74 mmol) in DMSO (10 mL) is addedbis(pinacolato)diboron (0.663 g, 2.61 mmol) and KOAc (0.682 g, 6.96mmol). The suspension is bubbled with nitrogen gas for 10 minutes andthen is treated with Pd(dppf)Cl₂ (20 mg) The mixture is then stirred andheated at 85° C. for 6 hours. The reaction is quenched water (50 mL) andextracted with EtOAc (50 mL×2) and the combined organics are dried(Na₂SO₄), concentrated and purified on silica gel chromatography columnwith 20% EtOAc/Hexanes to yield the title compound as yellowish oil(0.825 g, 87%). MS (ES): 548.3.

Example 1033-(4-{2-[4-Isopropyl-2-(4-pyrimidin-2-yl-phenyl)-oxazol-5-yl]-propoxy}-2-methyl-phenyl)-propionicacid

A solution of3-[4-(2-{4-isopropyl-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-oxazol-5-yl}-propoxy)-2-methyl-phenyl]-propionicacid methyl ester (91 mg, 0.166 mmol) in toluene (4.0 mL) is bubbledwith nitrogen gas for 10 minutes. To this, Pd(dppf)Cl₂ (10 mg), Na₂CO₃(1.0 mL, 2.0 M), 2-bromopyrimidine (53 mg, 0.333 mmol) are added. Theresulting suspension is stirred and heated at 90° C. for 48 hours. It isthen concentrated, purified on silica gel chromatography column with20–40% EtOAc/Hexanes to yield the pyrimidine intermediate.

The pyrimidine intermediate is dissolved in MeOH (1.0 mL) and THF (0.5mL) and treated with NaOH (1.5 mL, 2.0 M) and stirred at roomtemperature for 2 hours. The mixture is neutralized to pH=6 with HCl (5N) and extracted with EtOAc (20 mL×2), and the combined organics aredried (Na₂SO₄), concentrated and purified on silica gel chromatographycolumn with EtOAc/Hexanes/HOAc (50/50/2) to yield the acid as whitesolid (14 mg, 18%). MS (ES): 486.2; the structure is also confirmed byproton NMR.

The following compounds are made in a similar manner:

Example 1043-(4-{1-[4-Isopropyl-2-(4-pyridin-2-yl-phenyl)-oxazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionicacid

MS (ES): 485.2; the structure is also confirmed by proton NMR.

Example 1053-(4-{2-[4-Isopropyl-2-(4-pyrazin-2-yl-phenyl)-oxazol-5-yl]-propoxy}-2-methyl-phenyl)-propionicacid

MS (ES): 486.2; the structure is also confirmed by proton NMR.

Example 106(R)-3-(2-Methyl-4-{1-r[4-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethoxy}-phenyl)-propionicacid

Racemic3-(2-Methyl-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethoxy}-phenyl)-propionicacid methyl ester is separated into its enantiomers using Ethanol aseluent on a Chiralpak AD at 1.0 mL/min to afford(R)-3-(2-Methyl-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethoxy}-phenyl)-propionicacid methyl ester. Hydrolysis of the ester gave the title compound,(R)-3-(2-Methyl-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethoxy}-phenyl)-propionicacid as a white solid MS (M⁺+1) 434.

Example 107(S)-3-(2-Methyl-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethoxy}-phenyl)-propionicacid

Racemic3-(2-Methyl-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethoxy}-phenyl)-propionicacid methyl ester is separated into its enantiomers using Ethanol aseluent on a Chiralpak AD at 1.0 mL/min to afford(S)-3-(2-Methyl-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethoxy}-phenyl)-propionicacid methyl ester. Hydrolysis of the ester gave the title compound,(S11)-3-(2-Methyl-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethoxy}-phenyl)-propionicacid as a white solid MS (M⁺+1) 434.

The following compounds are made in a similar manner via chiralseparation:

Example 108(S)-3-(4-{2-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-propoxy}-2-methyl-phenyl)-propionicacid

The structure is confirmed by MS. MS (M⁺+1) 476.

Example 109(R)-3-(4-{2-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-propoxy}-2-methyl-phenyl)-propionicacid

The structure is confirmed by MS. MS (M⁺+1) 476.

Example 1103-(2-Methyl-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-butoxy}-phenyl)-propionicacid

3-(2-Methyl-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-but-3-enyloxy}-phenyl)-propionicacid (30 mg, 0.065 mmol), 10% Palladium on charcoal (30 mg) andtetrahydrofuran (30 mL) is stirred under a hydrogen balloon 30 min. Thesolution is filtered over celite and concentrated in vacuo to afford thetitle compound,3-(2-Methyl-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-butoxy}-phenyl)-propionicacid as a white solid, 30 mg 100%. MS (M⁺+1) 462.

Example 1113-(4-{1-[2-(4-bromo-phenyl)-4-isopropyl-oxazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionicacid methyl ester

To a solution of 1-[2-(4-bromo-phenyl)-4-isopropyl-oxazol-5-yl]-ethanol(9.05 g, 29.2 mmol) in toluene (300 ml) at 0° C. is addedtri-n-butylphosphine (7.70 g, 38.1 mmol) and1,1′-(azodicarbonyl)-dipiperidine (8.84 g, 35.0 mmol), followed byaddition of 3-(4-hydroxy-2-methyl-phenyl)-propionic acid methyl ester(6.30 g, 32.1 mmol). The resulting mixture is stirred for 18 hours whilewarmed up to room temperature. The reaction is quenched with water (100ml) and the aqueous layer is extracted with EtOAc (2×100 ml). Thecombined organics are dried over Na₂SO₄ and concentrated, purified bysilica gel chromatography (Hexanes/EtOAc, 9/1 to 8.5/1.5) to afford the3-(4-{1-[2-(4-bromo-phenyl)-4-isopropyl-oxazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionicacid methyl ester as a colorless oil (11.4 g, 80%). MS (MH+): 488.1.

Example 1123-[4-(1-{4-Isopropyl-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-oxazol-5-yl}-ethoxy)-2-methyl-phenyl]-propionicacid methyl ester

To a solution of3-(4-{1-[2-(4-bromo-phenyl)-4-isopropyl-oxazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionicacid methyl ester (2.50 g, 5.14 mmol) in DMSO (50 ml) is added thebis(pinacolato)diboron (1.88 g, 7.40 mmol) and potassium acetate (1.94g, 19.8 mmol). The suspension is bubbled with N₂ for 10 minutes, andthen Pd₂Cl₂ (dppf) is added. The mixture is stirred and heated to 85° C.for 4 hours. The reaction mixture is quenched with H₂O (100 mL) andextracted with EtOAc (3×100 mL). The combined organics are dried overNa₂SO₄ and concentrated, purified by silica gel chromatography(Hexanes/EtOAc, 8/2) to afford the borane intermediate as a colorlessoil (1.68 g, 61%). MS (MH+): 534.3.

Example 1133-(4-{1-[2-(4-Hydroxy-phenyl)-4-isopropyl-oxazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionicacid methyl ester

A solution of 3-[4-(1-{4-Isopropyl-2-[4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-phenyl]-oxazol-5-yl}-ethoxy)-2-methyl-phenyl]-propionicacid methyl ester (0.88 g, 1.69 mmol) in THF (5 ml) at 0° C. is treatedwith HOAc (150 mg, 2.54 mmol), followed by addition of mixture of H₂O₂(4.0 ml, 30%) in H₂O (0.8 ml). The reaction mixture is stirred for 2hours while warmed to room temperature. The mixture is then cooled backto 0° C. and treated with saturated aqueous Na₂S₂O₃ (30 ml) carefully.The mixture is then extracted with EtOAc (3×100 mL) and the combinedorganics are dried over Na₂SO₄ and concentrated, purified by silica gelchromatography (Hexanes/EtOAc, 7/3 to 5/5) to afford the phenol as acolorless oil (0.62 g, 87%). MS (MH+): 424.4.

Example 1143-(4-{1-[4-Isopropyl-2-(4-methoxy-phenyl)-oxazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionicacid

A solution of3-(4-{1-[2-(4-Hydroxy-phenyl)-4-isopropyl-oxazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionicacid methyl ester (42 mg, 0.10 mmol) in DMF (1.0 ml) is treated withiodomethane (0.20 ml) and K₂CO₃ (100 mg). The suspension is stirred atroom temperature for 24 hours and then quenched with water (5 ml). Themixture is then extracted with EtOAc (3×10 mL) and the combined organicsare dried over Na₂SO₄ and concentrated, purified by silica gelchromatography (Hexanes/EtOAc, 7/3) to afford the phenol ether as acolorless oil. The ester is then dissolved in MeOH (1.0 ml) and THF (0.5ml) and treated with NaOH (2.0 N, 1.5 ml). The mixture is stirred atroom temperature for 2 hours and concentrated to an aqueous residue. Itis then neutralized with 5 N HCl to pH-4 and extracted with EtOAc (3×5ml). The combined organics are dried over Na₂SO₄ and concentrated,purified by silica gel chromatography (Hexanes/EtOAc, 5/5, thenHexanes/EtOAc/HOAc 5/5/0.02) to afford the acid as a colorless oil (10mg, 25%). MS (MH+): 424.2.

The following compounds are made in a similar manner:

Example 1153-(4-{1-[4-Isopropyl-2-(3-methoxy-phenyl)-oxazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionicacid

MS (ES): 424.2 (M⁺+H).

Example 1163-(4-{1-[2-(3-Isopropoxy-phenyl)-4-isopropyl-oxazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionicacid

MS (ES): 452.3 (M⁺+H).

Example 1173-(4-{1-[2-(3-Cyclopentyloxy-phenyl)-4-isopropyl-oxazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionicacid

MS (ES): 478.3 (M⁺+H).

Example 1183-(4-{1-[2-(4-Isopropoxy-phenyl)-4-isopropyl-oxazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionicacid

MS (ES): 452.3 (M⁺+H).

Example 1193-[4-(1-{4-Isopropyl-2-[3-(tetrahydro-pyran-4-yloxy)-phenyl]-oxazol-5-yl}-ethoxy)-2-methyl-phenyl]-propionicacid

MS (ES): 494.2 (M⁺+H).

Example 1203-(4-{1-[2-(4-Cyclopentyloxy-phenyl)-4-isopropyl-oxazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionicacid

MS (ES): 478.3 (M⁺+H).

Example 1213-(4-{1-[4-Isopropyl-2-(3-methoxy-phenyl)-oxazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionicacid

MS (ES): 424.2; the structure is also confirmed by proton NMR.

Example 1223-(4-{1-[2-(3-Isopropoxy-phenyl)-4-isopropyl-oxazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionicacid

MS (ES): 452.3; the structure is also confirmed by proton NMR.

Example 1233-(4-{1-[2-(3-Cyclopentyloxy-phenyl)-4-isopropyl-oxazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionicacid

MS (ES): 478.3; the structure is also confirmed by proton NMR.

Example 1243-[4-(1-{4-Isopropyl-2-[4-(tetrahydro-pyran-4-yloxy)-phenyl]-oxazol-5-yl}-ethoxy)-2-methyl-phenyl]-propionicacid

MS (ES): 494.2; the structure is also confirmed by proton NMR.

Example 1253-(4-{1-[4-Isopropyl-2-(4-piperidin-1-yl-phenyl)-oxazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionicacid

A solution of3-(4-{1-[2-(4-bromo-phenyl)-4-isopropyl-oxazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionicacid methyl ester (97 mg, 0.200 mmol) in toluene (5 ml) is bubbled withnitrogen for 10 minutes. To this solution is added piperidine (34 mg,0.40 mmol), Pd(OAc)₂ (10 mg), 2-(di-t-butylphosphino)-biphenyl (10 mg)and sodium tert-butoxide (38 mg, 0.40 mmol). The suspension is heated to100° C. for 8 hours and quenched with water (5 ml). The mixture is thenextracted with EtOAc (3×10 mL) and the combined organics are dried overNa₂SO₄ and concentrated, purified by silica gel chromatography(Hexanes/EtOAc, 7.5/2.5) to afford the piperidine aniline intermediateas a colorless oil. The ester is then dissolved in MeOH (1.0 ml) and THF(0.5 ml) and treated with NaOH (2.0 N, 1.5 ml). The mixture is stirredat room temperature for 2 hours and concentrated to an aqueous residue.It is then neutralized with 5 N HCl to pH-4 and extracted with EtOAc(3×5 ml). The combined organics are dried over Na₂SO₄ and concentrated,purified by silica gel chromatography (Hexanes/EtOAc, 5/5, thenHexanes/EtOAc/HOAc 5/5/0.02) to afford the acid as a colorless oil (25mg, 26%). MS (ES): 477.3 (M⁺+1).

The following compounds are made in a similar manner:

Example 1263-(4-{1-[4-Isopropyl-2-(3-morpholin-4-yl-phenyl)-oxazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionicacid

MS (ES): 479.3 (M⁺+1).

Example 1273-(4-{1-[4-Isopropyl-2-(4-morpholin-4-yl-phenyl)-oxazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionicacid

MS (ES): 479.3 (M⁺+1).

Example 1283-(4-{1-[4-Isopropyl-2-(3-piperidin-1-yl-phenyl)-oxazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionicacid

MS (ES): 477.4; the structure is also confirmed by proton NMR.

Example 1293-{4-[1-(2-Biphenyl-4-yl-4-isopropyl-oxazol-5-yl)-ethoxy]-2-methyl-phenyl}-propionicacid

A solution of3-(4-{1-[2-(4-bromo-phenyl)-4-isopropyl-oxazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionicacid methyl ester (150 mg, 0.308 mmol) in toluene (4 ml) and THF (0.5ml) is bubbled with nitrogen for 10 minutes. To this solution is addedphenyl boronic acid (56 mg, 0.46 mmol), Pd(OAc)₂ (10 mg), and sodiumcarbonate (1.0 ml, 2.0 N). The suspension is heated to 85° C. for 8hours and the mixture is then extracted with EtOAc (3×10 mL). Thecombined organics are dried over Na₂SO₄ and concentrated, purified bysilica gel chromatography (Hexanes/EtOAc, 7.5/2.5) to afford thebiphenyl intermediate as a colorless oil. The ester is then dissolved inMeOH (1.0 ml) and THF (0.5 ml) and treated with NaOH (2.0 N, 1.5 ml).The mixture is stirred at room temperature for 2 hours and concentratedto an aqueous residue. It is then neutralized with 5 N HCl to pH˜4 andextracted with EtOAc (3×5 ml). The combined organics are dried overNa₂SO₄ and concentrated, purified by silica gel chromatography(Hexanes/EtOAc, 5/5, then Hexanes/EtOAc/HOAc 5/5/0.02) to afford theacid as a colorless oil (35 mg, 24%). MS (ES): 470.1 (M⁺+1).

Example 1303-{4-[1-(2-Biphenyl-3-yl-4-isopropyl-oxazol-5-yl)-ethoxy]-2-methyl-phenyl}-propionicacid

MS (ES): 470.2 (M⁺+1).

Example 1313-(4-{1-[2-(3′-Fluoro-biphenyl-4-yl)-4-isopropyl-oxazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionicacid

MS (ES): 488.2 (M⁺+1).

Example 1323-(4-{1-[4-Isopropyl-2-(4′-methoxy-biphenyl-4-yl)-oxazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionicacid

MS (ES) 500.2 (M⁺+1).

Example 133

3-(4-{1-[4-Isopropyl-2-(4-pyrimidin-2-yl-phenyl)-oxazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionicacid

A solution of3-[4-(1-{4-isopropyl-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-oxazol-5-yl}-ethoxy)-2-methyl-phenyl]-propionicacid methyl ester (130 mg, 0.250 mmol) in toluene (3 mL) is bubbled withnitrogen gas for 10 minutes. To this, Pd(dppf)Cl₂ (10 mg), Na₂CO₃ (1.0mL, 2.0 M), 2-chloropyrimidine (43 mg, 0.375 mmol) are added. Theresulting suspension is stirred and heated at 100° C. for 8 hours andquenched with water (1.0 mL). The mixture is extracted with EtOAc (20mL×2) and the combined organics are dried (Na₂SO₄), concentrated, andpurified on silica gel chromatography column with 20–50% EtOAc/Hexanesto yield the pyrimidine intermediate.

The pyrimidine intermediate is dissolved in MeOH (1.0 mL) and THF (0.5mL) and treated with NaOH (1.5 mL, 2.0 M) and stirred at roomtemperature for 12 hours. The mixture is neutralized to pH=6 with HCl (5N) and extracted with EtOAc (20 mL×2), and the combined organics aredried (Na₂SO₄), concentrated to yield the acid as white solid (3.0 mg,2.5%).

MS (ES): 472.3; the structure is also confirmed by proton NMR.

Example 134

3-(4-{1-[4-Isopropyl-2-(4-pyrimidin-5-yl-phenyl)-oxazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionicacid

MS (ES): 472.3; the structure is also confirmed by proton NMR.

Example 1353-(4-{1-[4-Isopropyl-2-(4-pyrazin-2-yl-phenyl)-oxazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionicacid

MS (ES): 472.3; the structure is also confirmed by proton NMR.

Example 1363-(4-{1-[2-(4-Hexylcarbamoyl-phenyl)-4-isopropyl-oxazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionicacid

To a solution of of3-(4-{1-[2-(4-bromo-phenyl)-4-isopropyl-oxazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionicacid methyl ester (280 mg, 0.576 mmol) in acetonitrile (30 ml) is addedthe Pd₂Cl₂ (dppf) (15 mg) and hexyl amine (117 mg, 1.15 mmol). Triethylamine (0.50 ml) is added and the mixture is stirred and heated to 75° C.under the balloon pressure of CO for 16 hours. The reaction mixture isfiltered through a pad of celite and purified by silica gelchromatography (Hexanes/EtOAc, 6/4) to afford the amide esterintermediate as a colorless oil. The ester is then dissolved in MeOH(1.0 ml) and THF (0.5 ml) and treated with NaOH (2.0 N, 1.5 ml). Themixture is stirred at room temperature for 2 hours and concentrated toan aqueous residue. It is then neutralized with 5 N HCl to pH-4 andextracted with EtOAc (3×5 ml). The combined organics are dried overNa₂SO₄ and concentrated, purified by chromato lab with HPLC to affordthe final product (3.9 mg, 1.3%).

Example 137(4-{2-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-propoxy}-2-methyl-phenyl)-aceticacid

Step A(4-{2-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-propoxy}-2-methyl-phenyl)-aceticacid methyl ester

A mixture of2-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-propan-1-ol,(0.18 g, 0.5745 mmol), (4-Hydroxy-2-methyl-phenyl)-acetic acid methylester (0.114 g) and toluene (10 mL) and azodicarboxylic dipiperidide(0.19 g, 0.747 mmol) is stirred at −20 deg C. Neat tri-n-butyl phosphine(0.19 mL, 0.747 mmol) is added dropwise and the resulting mixture isallowed to reach room temperature with stirring 18 hr. The mixture isdiluted with ether (25 mL) and cooled in ice/water for 30 min. Themixture is filtered, concentrated, and purified via silica gelchromatography eluting with 95:5 hexanes:ethyl acetate to afford thetitle compound as a thick oil, 0.065 g, 24%. MS M⁺+1 476. The structureis confirmed by ¹H NMR spectroscopy.

Step B(4-{2-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-propoxy}-2-methyl-phenyl)-aceticacid

(4-{2-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-propoxy}-2-methyl-phenyl)-aceticacid methyl ester (0.065 g, 0.1367 mmol), lithium hydroxide (0.020 g,0.8333 mmol) and 3:2:1 tetrahydrofuran:methanol:water (15 mL) is stirredat 60 deg C. 1 hr. The mixture is cooled on ice/water and diluted with0.2 N aqueous hydrochloric acid. The product is extracted to ethylacetate (2×50 mL), the extracts combined, dried over anhydrous magnesiumsulfate, filtered and concentrated to afford the title compound as awhite solid, 55 mg, 87%. MS M⁺+1 462. The structure is confirmed by ¹HNMR spectroscopy.

The following compounds are prepared in a similar manner.

Example 138(2-Methyl-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethoxy}-phenyl)-aceticacid

MS M⁺+1 420. The structure is confirmed by ¹H NMR spectroscopy.

Example 139(3-{2-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-propoxy}-phenyl)-aceticacid

Step A(3-{2-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-propoxy}-phenyl)-aceticacid methyl ester

Azodicarboxylic dipiperidide (0.31 g, 1.23 mmol) is stirred in 5 mLtoluene at −30 to −20 deg C. Tri-n-butyl phosphine (0.31 mL, 1.23 mmol)is added dropwise and the mixture is stirred at −30 to −20 deg C. 10–15min. An intimate mixture of (3-hydroxy-phenyl)-acetic acid methyl ester(0.13 g, 0.77 mmol) and2-[4-isopropyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-propan-1-ol(0.20 g, 0.701 mmol) in toluene (5 mL) is added dropwise and theresulting mixture is stirred 18 hr at room temperature. The thicksuspension is diluted with 25 mL ether and cooled on ice/water for 30min. The mixture is filtered, concentrated, and purified via silica gelchromatography eluting with 98:2 hexanes:acetone to afford the titlecompound as a colorless thick oil, 0.10 g, 31%. MS M⁺+1 462. Thestructure is confirmed by ¹H NMR spectroscopy.

Step B(3-{2-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-propoxy}-phenyl)-aceticacid

Hydrolysis of the ester from step A gave the title compound. MS M⁺+1448. The structure is confirmed by ¹H NMR spectroscopy.

The following examples are prepared in a similar manner:

Example 140(3-{1-[4-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethoxy}-phenyl)-aceticacid

MS M⁺+1 406. The structure is confirmed by ¹H NMR spectroscopy.

Example 141(3-{2-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-propoxy}-phenyl)-aceticacid, enantiomer 1

MS M⁺+1 419. The structure is confirmed by ¹H NMR spectroscopy.

Example 142(3-{2-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-propoxy}-phenyl)-aceticacid, enantiomer 2

MS M⁺+1 419. The structure is confirmed by ¹H NMR spectroscopy.

Example 143(3-{2-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-propoxy}-4-methoxy-phenyl)-aceticacid

MS M⁺+1 478. The structure is confirmed by ¹H NMR spectroscopy.

Example 1443-(3-{2-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-propoxy}-phenyl)-propionicacid

MS M⁺+1 462. The structure is confirmed by ¹H NMR spectroscopy.

The following example is prepared in a similar manner:

Example 1453-(3-{1-[4-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethoxy}-phenyl)-propionicacid

MS M⁺+1 420. The structure is confirmed by ¹H NMR spectroscopy.

Example 146(3-{2-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-propylsulfanyl}-phenyl)-aceticacid

MS M⁺+1 464. The structure is confirmed by ¹H NMR spectroscopy.

Example 147(3-{1-[4-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethylsulfanyl}-phenyl)-aceticacid

MS M⁺+1 422. The structure is confirmed by ¹H NMR spectroscopy.

Example 148(3-{1-Methyl-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethylsulfanyl}-phenyl)-aceticacid

Step A 2-[4-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-propan-2-ol

1-[4-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethanone (0.58 g,2.15 mmol) is stirred in tetrahydrofuran (25 mL) at zero deg. C. Methylmagnesium bromide (1.1 mL, 3.23 mmol, 3 M in ether) is added and thereaction stirred at room temperature 2 hr. The mixture is cooled onice/water and quenched with saturated ammonium chloride (5 mL). Theproduct is extracted with ethyl acetate (3×50 mL), dried over anhydrousmagnesium sulfate, filtered and concentrated to afford the product as atan solid, 0.40 g, 65%). MS M⁺+1 286. The structure is confirmed by ¹HNMR spectroscopy.

Step B(3-{1-Methyl-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethylsulfanyl}-phenyl)-aceticacid methyl ester

A mixture of2-[4-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-propan-2-ol (0.1g, 0.351 mmol), (3-Mercapto-phenyl)-acetic acid methyl ester (0.070 g,0.386 mmol), zinc (I) iodide (0.056 g, 0.176 mmol), and1,2-dichloroethane (2 mL) is stirred at room temperature 24 hr. Thereaction mixture is diluted with ethyl acetate (25 mL), and washed withaqueous saturated sodium hydrogen carbonate, water, brine (25 mL each),dried over anhydrous magnesium sulfate, filtered, concentrated, andpurified via silica chromatography eluting with 8:2 hexanes:ethylacetate to afford the product as a colorless film, 0.105 g, 66%. MS M⁺+1286. The structure is confirmed by ¹H NMR spectroscopy.

Step C(3-{1-Methyl-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethylsulfanyl}-phenyl)-aceticacid

MS M⁺+1 436. The structure is confirmed by ¹H NMR spectroscopy.

Example 1493-(2-Methyl-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethoxymethyl}-phenyl)-propionicacid

A mixture of1-[4-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethanol (0.132 g,0.487 mmol), sodium hydride (0.05 g, 1.25 mmol) and N,N-dimethylformamide (5 mL) is stirred at room temperature.3-(4-Iodomethyl-2-methyl-phenyl)-propionic acid methyl ester (0.17 g,0.535 mmol) is added and the mixture is heated to 65 deg C., 2 hr. Thereaction is cooled to room temperature and diluted with aqueous sodiumhydroxide (10 mL, 5M) and stirred 1 hr. The pH is adjusted with aqueoushydrochloric acid until pH is 2–3. The product is extracted into ethylacetate (3×25 mL). The combined extracts are dried over anhydrousmagnesium sulfate, filtered and concentrated. The residue is purifiedvia silica chromatography eluting with 7:3 hexanes:ethyl acetate to 1:1hexanes:ethyl acetate to afford the title compound as a white solid,0.027 g, 12%. MS M⁺+1 448. The structure is confirmed by ¹H NMRspectroscopy.

The following examples are prepared in a similar manner:

Example 1503-(4-{1-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethoxymethyl}-2-methyl-phenyl)-propionicacid

MS M⁺+1 476. The structure is confirmed by ¹H NMR spectroscopy.

Example 1513-(4-{2-[2-(4-Difluoromethyl-phenyl)-4-isopropyl-oxazol-5-yl]-propoxymethyl}-2-methyl-phenyl)-propionicacid

MS M⁺+1 472. The structure is confirmed by ¹H NMR spectroscopy.

Example 152(4-{2-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-propyl}-2-methyl-phenoxy)-aceticacid

Step A 5-Isopropenyl-4-isopropyl-2-(4-trifluoromethyl-phenyl)-oxazole

4-Isopropyl-2-(4-trifluoromethyl-phenyl)-oxazole-5-carboxylic acidmethyl ester (5.0 g, 15.3 mmol) and tetrahydrofuran (100 mL) are stirredin ice/water. Methyl magnesium bromide (12.7 mL, 38.2 mmol, 3M in ether)is added and the mixture is stirred at room temperature 3 hr. Thereaction is cooled on ice/water and quenched with aqueous saturatedammonium chloride (15 mL). The product is extracted into ethyl acetate(3×50 mL). The combined extracts are dried over anhydrous magnesiumsulfate, filtered, and concentrated. The residue is taken up in toluene(50 mL) and p-toluenesulfonic acid monohydrate (0.2 g, 1.05 mmol) isadded and the mixture is heated to reflux for 1 hr. The mixture isconcentrated and the residue is purified via silica chromatographyeluting the product with hexanes to afford the product as a yellowsolid, 4.17 g, 92%. MS M⁺+1 296. The structure is confirmed by ¹H NMRspectroscopy.

Step B(4-{2-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-propyl}-2-methyl-phenoxy)-aceticacid methyl ester

A mixture of5-Isopropenyl-4-isopropyl-2-(4-trifluoromethyl-phenyl)-oxazole (0.5 g,1.695 mmol), 9-BBN dimer (0.46 g, 1.865 mmol), and tetrahydrofuran (5mL) is stirred at room temperature 6 hr. The mixture is diluted withwater (1 mL). In another flask, a mixture of(4-bromo-2-methyl-phenoxy)-acetic acid methyl ester (0.53 g, 2.03 mmol),[1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) complexwith dichloromethane (1:1) (0.14 g, 0.17 mmol), triphenylarsine (0.1 g,0.339 mmol), and N,N-dimethylformamide (5 mL) is stirred in ice/water.The previously described 9-BBN solution is added via cannula and theresulting mixture is stirred at room temperature 18 hr. The blackreaction mixture is diluted with water (50 mL) and brine (50 mL), andthe product is extracted to ethyl acetate (3×75 mL). The combinedextracts are dried over anhydrous magnesium sulfate, filtered, andconcentrated. The black residue is purified via silica chromatographyeluting with 1:1 hexanes:dichloromethane to 1:1:0.5hexanes:dichloromethane:ethyl acetate to afford the product as acolorless oil, 0.136 g, 17%. MS M⁺+1 476. The structure is confirmed by¹H NMR spectroscopy.

Step C(4-{2-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-propyl}-2-methyl-phenoxy)-aceticacid

Hydrolysis of the ester from step B gave the title compound (0.015 g,75%). MS M⁺+1 462. The structure is confirmed by ¹H NMR spectroscopy.

Example 1533-(4-{2-[5-Ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-propionylamino}-2-methyl-phenyl)-propionicacid

Step A3-(4-{2-[5-Ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-propionylamino}-2-methyl-phenyl)-propionic-acidmethyl ester

To a mixture of2-[5-Ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-propionic acid(0.35 mmol), 3-(4-Amino-2-methyl-phenyl)-propionic acid methyl ester(0.35 mmol), and DMAP (0.01 g, 0.082 mmol) in CH₂Cl₂ (5 mL) is addedEDCI (0.08 g, 0.42 mmol). After stirring for 2 h at RT, the mixture isconcentrated. The residue is redissolved in EtOAc, and the organics arewashed with 1N HCl (1×), 2N NaOH (2×), water, and brine, and dried withMgSO₄. The crude material is purified by flash chromatography to yieldthe title compound.

Step B3-(4-{2-[5-Ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-propionylamino}-2-methyl-phenyl)-propionicacid

Hydrolysis of the product from step one in the presence of sodiumhydroxide gave the title compound. MS (ES): 491 (M⁺+1); the structure isalso confirmed by ¹H NMR.

Example 1543-[4-({2-[5-Ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-propionyl}-methyl-amino)-2-methyl-phenyl]-propionicacid

Step A3-[4-({2-[5-Ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-propionyl}-methyl-amino)-2-methyl-phenyl]-propionicacid methyl ester

To a solution of3-(4-{2-[5-Ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-propionylamino}-2-methyl-phenyl)-propionocacid methyl ester (0.09 g, 0.17 mmol) and methyl iodide (11 μL, 0.17mmol) in DMF is added NaH (12 mg, 0.29 mmol). The mixture is stirred atRT for 12 h. Water is added, and the mixture is extracted with EtOAc.The organics are washed with brine and dried with MgSO₄. The crudematerial is purified by flash chromatography to yield the title compound(65 mg, 75%).

Step B3-[4-({2-[5-Ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-propionyl}-methyl-amino)-2-methyl-phenyl]-propionicacid

A similar hydrolysis procedure is followed to yield the title compound(51 mg, 81%). MS (ES): 505 (M⁺+1); the structure is also confirmed by ¹HNMR.

Example 1553-(4-{2-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propylamino}-2-methyl-phenyl)-propionicacid TFA salt

Step A3-(4-{2-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propylamino}-2-methyl-phenyl)-propionicacid methyl ester

To a solution of 3-(4-Amino-2-methyl-phenyl)-propionic acid methyl ester(0.7.0 mmol) and2-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propionaldehyde(0.71 mmol) in anhydrous CH₂Cl₂ (5 mL) is added 4 Å molecular sievesfollowed by acetic acid (50 μL, 0.87 mmol). The mixture is stirred at RTfor 2 h. Sodium triacetoxyborohydride (0.22 g, 1.04 mmol) is added, andthe mixture is stirred at RT for 12 h. The reaction is quenched withsaturated NaHCO₃. The organics are separated and washed with saturatedNaHCO₃ and brine, and dried with MgSO₄. The crude material is purifiedby flash chromatography to yield the title compound (0.21 g, 68%).

Step B3-(4-{2-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propylamino}-2-methyl-phenyl)-propionicacid TFA salt

Hydrolysis of the ester product form step A foloowed by reversed phseHPLC purification gave the title compound. MS (ES): 491 (M⁺); thestructure is also confirmed by ¹H NMR.

Example 1563-{4-[({2-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propyl}-methyl-amino)-methyl]-2-methyl-phenyl}-propionicacid TFA salt

MS (ES): 519 (M⁺); the structure is also confirmed by ¹H NMR.

Example 1573-[4-(2-{2-[6-(2-Fluoro-phenyl)-pyridin-3-yl]-5-methyl-thiazol-4-yl}-propoxy)-2-methyl-phenyl]-propionicacid

Step A 6-(2-Fluoro-phenyl)-nicotinonitrile

A mixture of 6-Chloro-nicotinonitrile (7.26 g, 52.4 mmol) and2-fluorophenyl boronic acid (11 g, 78.6 mmol) and Na2CO3 (11 g, 103mmol) in toluene (200 mL) and water (10 mL) is degassed and filled withnitrogen for three times, then Pd(PPh3)4 (0.73 g) is added undernitrogen. The reaction mixture is heated at 90° C. After 12 hrs, thereaction mixture is cooled to room temperature, diluted with ethylacetate, washed with water, dried, concentrated. Column chromatographyon silica gel (Hexane/ethyl acetate as eluent) gave 9.8 g of6-(2-Fluoro-phenyl)-nicotinonitrile.

Step B 6-(2-Fluoro-phenyl)-thionicotinamide

A mixture of 6-(2-Fluoro-phenyl)-nicotinonitrile (9.8 g, 49.4 mmol) andthioacetamide (5.94 g, 79.1 mmol) in 4.0 M HCl in dioxane (200 mL) isheated at 100° C. for 3 days, cooled to room temperature. The ractionmixture is poured into old saturated sodium bicarbonate and stirred for30 min. Solid product is collected by filtration and dried under vacuumgiving the title compound (11.4 g).

Step C2-{2-[6-(2-Fluoro-phenyl)-pyridin-3-yl]-5-methyl-thiazol-4-yl}-propionicacid ethyl ester

A mixture of 6-(2-Fluoro-phenyl)-thionicotinamide (3.0 g, 12 mmol) and4-bromo-3-oxo-2-methyl-pentanoic acid methyl ester (3.2 g, 14.4 mmol) inethanol (100 mL) is heated to reflux for 24 h, and concentrated. Theresidue is purified by column chromatography on silica gel yielding 2.6g of the product.

Step D2-{2-[6-(2-Fluoro-phenyl)-pyridin-3-yl]-5-methyl-thiazol-4-yl}-propan-1-ol

To a solution of2-{2-[6-(2-Fluoro-phenyl)-pyridin-3-yl]-5-methyl-thiazol-4-yl}-propionicacid ethyl ester (2.6 g, 7.03 mmol) in THF (15 mL) is added LiAlH4 (1.0M in THF, 7.1 mL, 7.1 mmol) at 0–5° C., and then stirred for 2 h. Thereaction is then quenched by water and 5 N NaOH, diluted with THF andfiltered through a pad of celite. The filtrate is concentrated andpurified by column yielding 1.8 g of the product.

Step E3-[4-(2-{2-[6-(2-Fluoro-phenyl)-pyridin-3-yl]-5-methyl-thiazol-4-yl}-ethoxy)-2-methyl-phenyl]-propionicacid tert-butyl ester

A solution of 3-(4-hydroxy-2-methyl-phenyl)-propionic acid tert-butylester (120 mg, 0.5 mmol) and2-{2-[6-(2-fluoro-phenyl)-pyridin-3-yl]-5-methyl-thiazol-4-yl}-ethanol(106 mg, 0.323 mmol) in toluene (3.0 mL) is degassed and filled withnitrogen for 3 times. Tributylphosphine (0.124 mL, 0.5 mmol) is added tothe reaction mixture under nitrogen at 0° C., followed by addition of of1,1′-(azodicarbonyl)-dipiperidine (120 mg, 0.5 mmol). The reactionmixture is allowed to warm to room temperature and stirred overnight,the mixture is loaded on silica gel column. Chromatography gave thetitle compound (150 mg).

Step F3-[4-(2-{2-[6-(2-Fluoro-phenyl)-pyridin-3-yl]-5-methyl-thiazol-4-yl}-propoxy)-2-methyl-phenyl]-propionicacid

To a solution of3-[4-(2-{2-[6-(2-Fluoro-phenyl)-pyridin-3-yl]-5-methyl-thiazol-4-yl}-ethoxy)-2-methyl-phenyl]-propionicacid tert-butyl ester (120 mg) in methylene chloride (1 mL) is added TFA(0.8 mL) and two drops of water. The mixture is stirred for 2 h, andconcentrated and purified by reversed phase HPLC (water-acetonitrilewith 0.1% TFA). MS (ES): 491.4 (M⁺+1).

The following compounds are made in substantially similar method:

Example 1583-[4-(2-{2-[6-(3-Fluoro-phenyl)-pyridin-3-yl]-5-methyl-thiazol-4-yl}-propoxy)-2-methyl-phenyl]-propionicacid

MS (ES): 491.3 (M⁺+1).

Example 1593-[4-(2-{2-[6-(4-Fluoro-phenyl)-pyridin-3-yl]-5-methyl-thiazol-4-yl}-propoxy)-2-methyl-phenyl]-propionicacid

MS (ES): 491.3 (M⁺+1).

Example 1603-[4-(2-{2-[6-phenyl-pyridin-3-yl]-5-methyl-thiazol-4-yl}-propoxy)-2-methyl-phenyl]-propionicacid

MS (ES): 473.5 (M⁺+1).

Example 1613-[4-(2-{2-[6-(2-Methyl-phenyl)-pyridin-3-yl]-5-methyl-thiazol-4-yl}-propoxy)-2-methyl-phenyl]-propionicacid

MS (ES): 487.4 (M⁺+1).

Example 1623-[4-(2-{2-[6-(3-Methyl-phenyl)-pyridin-3-yl]-5-methyl-thiazol-4-yl}-propoxy)-2-methyl-phenyl]-propionicacid

MS (ES): 487.5 (M⁺+1).

Example 1633-[4-(2-{2-[6-(4-Methyl-phenyl)-pyridin-3-yl]-5-methyl-thiazol-4-yl}-propoxy)-2-methyl-phenyl]-propionicacid

MS (ES): 487.5 (M⁺+1).

Example 1643-{4-[2-(2-[2,2′]Bipyridinyl-5-yl-5-methyl-thiazol-4-yl)-propoxy]-2-methyl-phenyl}-propionicacid

MS (ES): 474.4 (M⁺+1).

Example 1653-(2-Methyl-4-{2-[5-methyl-2-(6-phenoxy-pyridin-3-yl)-thiazol-4-yl]-propoxy}-phenyl)-propionicacid

MS (ES): 489.5 (M⁺+1).

Example 1663-(2-Methyl-4-{2-[5-methyl-2-(4-pyridin-2-yl-phenyl)-oxazol-4-yl]-propoxy}phenyl)propionicacid

Step A3-(2-Methyl-4-{2-[5-methyl-2-(4-pyridin-2-yl-phenyl)-oxazol-4-yl]-propoxy}phenyl)propionicacid methyl ester

3-(4-{2-[2-(4-Bromo-phenyl)-5-methyl-oxazol-4-yl]-propoxy}-2-methylphenyl)-propionicacid methyl ester (592 mg, 1.25 mmol) is dissolved in anhydrous toluene(5 mL), degassed, and filled with nitrogen three times. Palladiumtetrakis triphenyl phosphine [Pd(PPh₃)₄, 25 mg, 0.025 mmol] is added,and the degassing procedure is repeated. 2-tributylstannylpyridine (635uL, 2.5 mmol) is then added via syringe and the reaction is heated toreflux. The reaction is monitored by HPLC. Upon complete consumption ofstarting material, the reaction is allowed to cool to room temperatureand diluted with ethyl acetate. Celite is added and the mixture isfiltered and rinsed with more ethyl acetate and water. The solution isfurther diluted with water and the two phases are separated. The organiclayer is washed with water and brine, dried over anhydrous sodiumsulfate, filtered, and concentrated. The pure3-(2-Methyl-4-{2-[5-methyl-2-(4-pyridin-2-yl-phenyl)-oxazol-4-yl]-propoxy}-phenyl)-propionicacid methyl ester is obtained after column chromatography.

Step B

3-(2-Methyl-4-{2-[5-methyl-2-(4-pyridin-2-yl-phenyl)-oxazol-4-yl]-propoxy}-phenyl)-propionicacid methyl ester from step A is dissolved in tetrahydrofuran (1 mL) and5N sodium hydroxide (1 mL) solution is added with stirring at roomtemperature. The reaction is heated to reflux and monitored by HPLC.Upon complete conversion, the reaction is allowed to cool to roomtemperature and neutralized with 5N hydrochloric acid (1 mL), dilutedwith ethyl acetate, and extracted. The organic layer is washed withwater and brine, dried over anhydrous sodium sulfate, filtered, andconcentrated. The pure3-(2-Methyl-4-{2-[5-methyl-2-(4-pyridin-2-ylphenyl)oxazol-4yl]propoxy}phenyl)propionicacid (400 mg, 0.875 mmol) may also be obtained by recrystalization fromethyl acetate. 70% yield 2 steps, MS (ES): 457.2 (M⁺+1).

The following compounds are made in a similar manner:

Example 1673-(2-Methyl-4-{2-[5-methyl-2-(4-pyridin-2-yl-phenyl)-oxazol-4-yl]-butoxy}-phenyl)-propionicacid

MS (ES): 471.3 (M⁺+1).

Example 1683-(2-Methyl-4-{1-methyl-2-[5-methyl-2-(4-pyridin-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid

MS (ES): 457.3 (M⁺+1).

Example 1693-(2-Methyl-4-{2-[5-methyl-2-(4-pyridin-2-yl-phenyl)-thiazol-4-yl]-propoxy}-phenyl)-propionicacid, HCl salt

MS (ES): 457.3 (M⁺+1-HCl).

Example 1703-(2-Methyl-4-{2-[5-methyl-2-(4-pyridin-2-yl-phenyl)-thiazol-4-yl]-butoxy}-phenyl)-propionicacid, HCl salt

MS (ES): 487.5 (M⁺1-HCl).

Example 1713-(2-Methyl-4-{2-[5-methyl-2-(4-pyrimidin-2-yl-phenyl)-thiazol-4-yl]-propoxy}-phenyl)-propionicacid

Step A3-[2-Methyl-4-(2-{5-methyl-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-thiazol-4-yl}-propoxy)-phenyl]-propionicacid methyl ester

3-(4-{2-[2-(4-Bromo-phenyl)-5-methyl-thiazol-4-yl]-propoxy}-2-methyl-phenyl)-propionicacid methyl ester (3.38 g, 6.92 mmol) is dissolved in anhydrous methylsulfoxide (25 mL), degassed, and filled with nitrogen three times.[1,1′-Bis-(diphenylphosphino)ferrocene]dichloropalladium(II) (330 mg,0.346 mmol) bis(pinacolato)diboron (3.5 g, 13.84 mmol), and potassiumacetate (2.0 g, 20.7 mmol) are added, and the degassing procedure isrepeated. The reaction is heated to 90° C. and monitored by HPLC. Uponcomplete consumption of starting material, the reaction is allowed tocool to room temperature and diluted with ethyl acetate. Celite is addedand the mixture is filtered and rinsed with more ethyl acetate andwater. The solution is further diluted with water and the two phases areseparated. The organic layer is washed with water and brine, dried overanhydrous sodium sulfate, filtered, and concentrated. The pure3-[2-Methyl-4-(2-{5-methyl-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-thiazol-4-yl}-propoxy)-phenyl]-propionicacid methyl ester (5.2 g, 6.92 mmol) is obtained after columnchromatography. 200% yield.

Step B3-(2-Methyl-4-{2-[5-methyl-2-(4-pyrimidin-2-yl-phenyl)-thiazol-4-yl]-propoxy}-phenyl)-propionicacid methyl ester

3-[2-Methyl-4-(2-(5-methyl-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-thiazol-4-yl)-propoxy)-phenyl]-propionicacid methyl ester (5.2 g, 6.92 mmol) is dissolved in anhydrous toluene(30 mL), degassed, and filled with nitrogen three times.[1,1′-Bis-(diphenylphosphino)ferrocene]dichloropalladium(II) (330 mg,0.346 mmol), 2-bromopyrimidine (2.24 g, 14 mmol), and sodium carbonate(3.71 g in 5 mL water, 35 mmol) are added, and the degassing procedureis repeated. The reaction is heated to 100° C. and monitored by HPLC.Upon complete consumption of starting material, the reaction is allowedto cool to room temperature and diluted with ethyl acetate. Celite isadded and the mixture is filtered and rinsed with more ethyl acetate andwater. The solution is further diluted with water and the two phases areseparated. The organic layer is washed with water and brine, dried overanhydrous sodium sulfate, filtered, and concentrated. The pure3-(2-Methyl-4-{2-[5-methyl-2-(4-pyrimidin-2-yl-phenyl)-thiazol-4-yl]-propoxy}-phenyl)-propionicacid methyl ester (1.3 g, 2.87 mmol) is obtained after columnchromatography (65% yield).

Step C

3-(2-Methyl-4-{2-[5-methyl-2-(4-pyrimidin-2-yl-phenyl)-thiazol-4-yl]-propoxy}-phenyl)-propionicacid methyl ester (698 mg, 1.43 mmol) is dissolved in tetrahydrofuran (2mL) and 5N sodium hydroxide (2 mL) solution is added with stirring atroom temperature. The reaction is heated to reflux and monitored byHPLC. Upon complete conversion, the reaction is allowed to cool to roomtemperature and neutralized with 5N hydrochloric acid (2 mL), dilutedwith ethyl acetate, and extracted. The organic layer is washed withwater and brine, dried over anhydrous sodium sulfate, filtered, andconcentrated. The pure3-(2-Methyl-4-{2-[5-methyl-2-(4-pyrimidin-2-yl-phenyl)-thiazol-4-yl]-propoxy}-phenyl)-propionicacid (462 mg, 0.9755 mmol) may also be obtained by recrystalization fromethyl acetate (68% yield), MS (ES): ?? (M⁺+1).

The following compounds are made in a similar manner:

Example 1723-[2-Methyl-4-(2-{4-methyl-2-[4-(3-methyl-pyridin-2-yl)-phenyl]-thiazol-5-yl}-propoxy)-phenyl]-propionicacid

MS (ES) 487.2 (M⁺+1).

Example 1733-[2-Methyl-4-(2-{4-methyl-2-[4-(5-methyl-pyridin-2-yl)-phenyl]-thiazol-5-yl}-propoxy)-phenyl]-propionicacid

MS (ES): 487.3 (M⁺+1).

Example 1743-(2-Methyl-4-{2-[4-methyl-2-(4-pyridin-2-yl-phenyl)-thiazol-5-yl]-propoxy}-phenyl)-propionicacid

MS (ES): 473.2 (M⁺+1).

Example 1753-[2-Methyl-4-(2-{5-methyl-2-[4-(6-methyl-pyridin-2-yl)-phenyl]-oxazol-4-yl}-propoxy)-phenyl]-propionicacid, HCl salt

MS (ES): 471.2 (M⁺+1-HCl).

Example 1763-[2-Methyl-4-(2-{5-methyl-2-[4-(5-methyl-pyridin-2-yl)-phenyl]-oxazol-4-yl}-propoxy)-phenyl]-propionicacid, HCl salt

MS (ES): 471.2 (M⁺+1-HCl).

Example 1773-[2-Methyl-4-(2-{5-methyl-2-[4-(3-methyl-pyridin-2-yl)-phenyl]-oxazol-4-yl}-propoxy)-phenyl]-propionicacid, HCl salt

MS (ES): 471.2 (M⁺+1-HCl).

Example 1783-[2-Methyl-4-(2-{5-methyl-2-[4-(5-trifluoromethyl-pyridin-2-yl)-phenyl]-oxazol-4-yl}-propoxy)-phenyl]-propionicacid, HCl salt

MS (ES) 525.6 (M⁺+1-HCl).

Example 1793-(4-{2-[4-Isopropyl-2-(4-pyridin-3-yl-phenyl)-thiazol-5-yl]-propoxy}-2-methyl-phenyl)-propionicacid, HCl salt

Step A

3-(4-{2-[2-(4-Bromo-phenyl)-4-isopropyl-thiazol-5-yl]-propoxy}-2-methyl-phenyl)-propionicacid methyl ester (333 mg, 0.645 mmol) is dissolved in toluene (3 mL),degassed, and filled with nitrogen three times. Palladiumtetrakistriphenyl phosphine (10 mg, 0.010 mmol), 3-pyridylboronic acid(159 mg, 1.29 mmol), and sodium carbonate (320 uL of a 10M solution,3.22 mmol) are added, and the degassing procedure is repeated. Ethanol(1 mL) is added to dissolve the boronic acid. The reaction is heated to100° C. and monitored by HPLC. Upon complete consumption of startingmaterial, the reaction is allowed to cool to room temperature anddiluted with ethyl acetate. Celite is added and the mixture is filteredand rinsed with more ethyl acetate and water. The solution is furtherdiluted with water and the two phases are separated. The organic layeris washed with water and brine, dried over anhydrous sodium sulfate,filtered, and concentrated. The pure3-(4-{2-[4-Isopropyl-2-(4-pyridin-3-yl-phenyl)-thiazol-5-yl]-propoxy)-}-2-methyl-phenyl)-propionicacid methyl ester is obtained after column chromatography.

Step B

3-(4-{2-[4-Isopropyl-2-(4-pyridin-3-yl-phenyl)-thiazol-5-yl]-propoxy}-2-methyl-phenyl)-propionicacid methyl ester from step A is dissolved in tetrahydrofuran (1 mL) and5N sodium hydroxide (1 mL) solution is added at room temperature. Thereaction is heated to reflux and monitored by HPLC. Upon completeconversion, the reaction is allowed to cool to room temperature andneutralized with 5N hydrochloric acid (1 mL), diluted with ethylacetate, and extracted. The organic layer is washed with water andbrine, dried over anhydrous sodium sulfate, filtered, and concentrated.The pure3-(4-{2-[4-Isopropyl-2-(4-pyridin-3-yl-phenyl)-thiazol-5-yl]-propoxy}-2-methyl-phenyl)-propionicacid (86 mg, 0.172 mmol, 27% yield) may also be obtained byrecrystalization from ethyl acetate. MS (ES): 501.1 (M⁺+1-HCl).

The following compound is made in a similar manner:

Example 1803-(4-{2-[4-Isopropyl-2-(4-pyridin-4-yl-phenyl)-thiazol-5-yl]-propoxy}-2-methyl-phenyl)-propionicacid, HCl salt

MS (ES): 501.1 (M⁺+1-HCl).

Example 1813-(2-Methyl-4-{2-[5-methyl-2-(4-phenylsulfanyl-phenyl)-oxazol-4-yl]-propoxy}-phenyl)-propionicacid

Step A

A solution of2-[5-Methyl-2-(4-phenylsulfanyl-phenyl)-oxazol-4-yl]-propan-1-ol (457mg, 1.40 mmol) in anhydrous toluene (20 mL) is degassed and filled withnitrogen for three times, and cooled to 0° C. in an ice water bath.Tri-n-butylphosphine (530 uL, 2.1 mmol) is added to the reaction mixtureunder nitrogen at 0° C., followed by addition of of1,1′-(azodicarbonyl)-dipiperidine (530 mg, 2.1 mmol), and3-(4-Hydroxy-2-methyl-phenyl)-propionic acid methyl ester (339 mg, 1.75mmol). The reaction mixture is allowed to warm to room temperature andstirred overnight, the mixture is loaded on silica gel column.Chromatography gave3-(2-Methyl-4-{2-[5-methyl-2-(4-phenyl-sulfanyl-phenyl)-oxazol-4-yl]-propoxy)-phenyl)-propionicacid methyl ester.

Step B

3-(2-Methyl-4-{2-[5-methyl-2-(4-phenyl-sulfanyl-phenyl)-oxazol-4-yl]-propoxy}-phenyl)-propionicacid methyl ester from step A is dissolved in tetrahydrofuran (1 mL) and5N sodium hydroxide (1 mL) solution is added with stirring at roomtemperature. The reaction is heated to reflux and monitored by HPLC.Upon complete conversion, the reaction is allowed to cool to roomtemperature and neutralized with 5N hydrochloric acid (1 mL), dilutedwith ethyl acetate, and extracted. The organic layer is washed withwater and brine, dried over anhydrous sodium sulfate, filtered, andconcentrated. The pure3-(2-Methyl-4-(2-[5-methyl-2-(4-phenylsulfanyl-phenyl)-oxazol-4-yl]-propoxy}-phenyl)-propionicacid (150 mg, 0.308 mmol) may also be obtained by recrystalization fromethyl acetate (22% yield 2 steps), MS (ES): 489.2 (M⁺+1).

The following compounds are made in a similar manner:

Example 182(S)-3-(2-Methyl-4-{2-[5-methyl-2-(4-phenylsulfanyl-phenyl)-oxazol-4-yl]-propoxy}-phenyl)-propionicacid

MS (ES) 489.1 (M⁺+1).

Example 183(R)-3-(2-Methyl-4-{2-[5-methyl-2-(4-phenylsulfanyl-phenyl)-oxazol-4-yl]-propoxy}-phenyl)-propionicacid

MS (ES): 489.1 (M⁺+1).

Example 1843-(2-Methyl-4-{2-[5-methyl-2-(4-phenylsulfanyl-phenyl)-oxazol-4-yl]-propoxy}-phenyl)-propionicacid

MS (ES): 473.6 (M⁺+1).

Example 1853-(2-Methyl-4-{2-[5-methyl-2-(6-phenyl-pyridin-3-yl)-oxazol-4-yl]-propoxy}-phenyl)-propionicacid

MS (ES): 457.2 (M⁺+1).

Example 1863-(4-{2-[4-Isopropyl-2-(4-pyrimidin-2-yl-phenyl)-oxazol-5-yl]-propoxy}-2-methyl-phenyl)-propionicacid

Step A3-(4-{2-[2-(4-Bromo-phenyl)-4-isopropyl-oxazol-5-yl]-propoxy}-2-methyl-phenyl)-propionicacid methyl ester

A solution of 2-[2-(4-bromo-phenyl)-4-isopropyl-oxazol-5-yl]-propan-1-ol(225 mg, 0.694 mmol) and 3-(4-hydroxy-2-methyl-phenyl)-propionic acidmethyl ester (190 mg, 0.972 mmol) in toluene (15 mL) is degassed andfilled with nitrogen for 3 times. Tributylphosphine (224 mg, 1.11 mmol)is added to the reaction mixture under nitrogen at 0° C., followed byaddition of of 1,1′-(azodicarbonyl)-dipiperidine (280 mg, 1.11 mmol).The reaction mixture is allowed to warm to room temperature and stirredovernight, the mixture is loaded directly on silica gel columnchromatography with 10–15% EtOAc/Hexanes to afford the title compound(320 mg, 92%).

Step B3-[4-(2-{4-Isopropyl-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-oxazol-5-yl}-propoxy)-2-methyl-phenyl]-propionicacid methyl ester

To a solution of3-(4-{2-[2-(4-Bromo-phenyl)-4-isopropyl-oxazol-5-yl]-propoxy}-2-methyl-phenyl)-propionicacid methyl ester (0.871 g, 1.74 mmol) in DMSO (10 mL) is addedbis(pinacolato)diboron (0.663 g, 2.61 mmol) and KOAc (0.682 g, 6.96mmol). The suspension is bubbled with nitrogen gas for 10 minutes andthen is treated with Pd(dppf)Cl₂ (20 mg) The mixture is then stirred andheated at 85° C. for 6 hours. The reaction is quenched water (50 mL) andextracted with EtOAc (50 mL×2) and the combined organics are dried(Na₂SO₄), concentrated and purified on silica gel chromatography columnwith 20% EtOAc/Hexanes to yield the title compound as yellowish oil(0.825 g, 87%). MS (ES): 548.3.

Step C3-(4-{2-[4-Isopropyl-2-(4-pyrimidin-2-yl-phenyl)-oxazol-5-yl]-propoxy}-2-methyl-phenyl)-propionicacid

A solution of3-[4-(2-{4-isopropyl-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-oxazol-5-yl}-propoxy)-2-methyl-phenyl]-propionicacid methyl ester (91 mg, 0.166 mmol) in toluene (4.0 mL) is bubbledwith nitrogen gas for 10 minutes. To this, Pd(dppf)Cl₂ (10 mg), Na₂CO₃(1.0 mL, 2.0 M), 2-bromopyrimidine (53 mg, 0.333 mmol) are added. Theresulting suspension is stirred and heated at 90° C. for 48 hours. It isthen concentrated, purified on silica gel chromatography column with20–40% EtOAc/Hexanes to yield the pyrimidine intermediate.

The pyrimidine intermediate is dissolved in MeOH (1.0 mL) and THF (0.5mL) and treated with NaOH (1.5 mL, 2.0 M) and stirred at roomtemperature for 2 hours. The mixture is neutralized to pH=6 with HCl (5N) and extracted with EtOAc (20 mL×2), and the combined organics aredried (Na₂SO₄), concentrated and purified on silica gel chromatographycolumn with EtOAc/Hexanes/HOAc (50/50/2) to yield the acid as whitesolid (14 mg, 18%). MS (ES): 486.2; the structure is also confirmed byproton NMR.

The following compounds are made in a similar manner:

Example 1873-(4-{1-[4-Isopropyl-2-(4-pyridin-2-yl-phenyl)-oxazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionicacid

MS (ES): 485.2; the structure is also confirmed by proton NMR.

Example 1883-(4-{2-[4-Isopropyl-2-(4-pyrazin-2-yl-phenyl)-oxazol-5-yl]-propoxy}-2-methyl-phenyl)-propionicacid

MS (ES): 486.2; the structure is also confirmed by proton NMR.

Example 1893-(4-{1-[4-Isopropyl-2-(4-pyrimidin-2-yl-phenyl)-oxazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionicacid

Step A3-(4-{1-[2-(4-Bromo-phenyl)-4-isopropyl-oxazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionicacid methyl ester

A solution of 3-(4-hydroxy-2-methyl-phenyl)-propionic acid methyl ester(6.30 g, 32.1 mmol) and1-[2-(4-bromo-phenyl)-4-isopropyl-oxazol-5-yl]-ethanol (9.05 g, 29.2mmol) in toluene (300 mL) is degassed and filled with nitrogen for 3times. Tributylphosphine (7.70 g, 38.1 mmol) is added to the reactionmixture under nitrogen at 0° C., followed by addition of of1,1′-(azodicarbonyl)-dipiperidine (8.84 g, 35.0 mmol). The reactionmixture is allowed to warm to room temperature and stirred overnight,the mixture is loaded directly on silica gel column chromatography with10–15% EtOAc/Hexanes to afford the title compound (11.8 g, 79%).

Step B

3-[4-(1-{4-Isopropyl-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-oxazol-5-yl}-ethoxy)-2-methyl-phenyl]-propionicacid methyl ester

To a solution of3-(4-{1-[2-(4-bromo-phenyl)-4-isopropyl-oxazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionicacid methyl ester (2.50 g, 5.14 mmol) in DMSO (50 mL) is addedbis(pinacolato)diboron (1.88 g, 7.40 mmol) and KOAc (1.94 g, 19.8 mmol).The suspension is bubbled with nitrogen gas for 10 minutes and then istreated with Pd(dppf)Cl₂ (100 mg) The mixture is then stirred and heatedat 85° C. for 4 hours. The reaction is quenched water and extracted withEtOAc (50 mL×3) and the combined organics are dried (Na₂SO₄),concentrated and purified on silica gel chromatography column with10–20% EtOAc/Hexanes to yield the title compound as yellow oil (1.68 g,61%).

Step C3-(4-{1-[4-Isopropyl-2-(4-pyrimidin-2-yl-phenyl)-oxazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionicacid

A solution of3-[4-(1-{4-isopropyl-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-oxazol-5-yl}-ethoxy)-2-methyl-phenyl]-propionicacid methyl ester (130 mg, 0.250 mmol) in toluene (3 mL) is bubbled withnitrogen gas for 10 minutes. To this, Pd(dppf)Cl₂ (10 mg), Na₂CO₃ (1.0mL, 2.0 M), 2-chloropyrimidine (43 mg, 0.375 mmol) are added. Theresulting suspension is stirred and heated at 100° C. for 8 hours andquenched with water (1.0 mL). The mixture is extracted with EtOAc (20mL×2) and the combined organics are dried (Na₂SO₄), concentrated, andpurified on silica gel chromatography column with 20–50% EtOAc/Hexanesto yield the pyrimidine intermediate.

The pyrimidine intermediate is dissolved in MeOH (1.0 mL) and THF (0.5mL) and treated with NaOH (1.5 mL, 2.0 M) and stirred at roomtemperature for 12 hours. The mixture is neutralized to pH=6 with HCl (5N) and extracted with EtOAc (20 mL×2), and the combined organics aredried (Na₂SO₄), concentrated to yield the acid as white solid (3.0 mg,2.5%). MS (ES): 472.3; the structure is also confirmed by proton NMR.

The following compounds are made in a similar manner:

Example 1903-(4-{1-[4-Isopropyl-2-(4-pyrimidin-5-yl-phenyl)-oxazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionicacid

MS (ES): 472.3; the structure is also confirmed by proton NMR.

Example 1913-(4-{1-[4-Isopropyl-2-(4-pyrazin-2-yl-phenyl)-oxazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionicacid

MS (ES): 472.3; the structure is also confirmed by proton NMR.

Example 1923-(4-{2-[4-Isopropyl-2-(4-pyrimidin-5-yl-phenyl)-thiazol-5-yl]-propoxy}-2-methyl-phenyl)-propionicacid

MS (ES): 502.1 (M⁺+1).

Example 1933-(2-Methyl-4-{2-[5-methyl-2-(4-pyrimidin-2-yl-phenyl)-oxazol-4-yl]-propoxy}-phenyl)-propionicacid

MS (ES): 458.2 (M⁺+1).

Example 1943-(2-Methyl-4-{2-[5-methyl-2-(4-pyrimidin-2-yl-phenyl)-thiazol-4-yl]-propoxy}-phenyl)-propionicacid

MS (ES): 447.0 (M⁺+1).

Example 1953-(2-Methyl-4-{2-[4-methyl-2-(4-pyrimidin-2-yl-phenyl)-oxazol-5-yl]-propoxy}-phenyl)-propionicacid

MS (ES): 458.3 (M⁺+1).

Example 1963-(2-Methyl-4-{2-[4-methyl-2-(4-pyrimidin-2-yl-phenyl)-thiazol-5-yl]-propoxy}-phenyl)-propionicacid

MS (ES): 474.2 (M⁺+1).

Example 1973-(2-Methyl-4-{2-[5-methyl-2-(4-pyrimidin-2-yl-phenyl)-oxazol-4-yl]-butoxy}-phenyl)-propionicacid

MS (ES): 472.3 (M⁺++1).

Example 1983-(2-Methyl-4-{2-[5-methyl-2-(4-pyrimidin-2-yl-phenyl)-thiazol-4-yl]-propoxy}-phenyl)-propionicacid

The racemic3-(2-methyl-4-{2-[5-methyl-2-(4-pyrimidin-2-yl-phenyl)-thiazol-4-yl]-propoxy}-phenyl)-propionicacid methyl ester is resolved on a Chiralpak AD column (4.6×250 mm).Eluted with 15% 3A in heptane with 0.2% dimethy-ethylamine at 1 mL perminute with detection at 300 nM and concentrated the fractions toprovide the pure enantiomer esters (isomer 1, 99.8% ee; isomer 2, 97.8%ee).

The following compounds are made in a similar manner:

Example 199(R)-3-(2-Methyl-4-{2-[5-methyl-2-(4-pyridin-2-yl-phenyl)-thiazol-4-yl]-propoxy}-phenyl)-propionicacid

MS (ES): 473.2 (M⁺+1).

Example 200(S)-3-(2-Methyl-4-{2-[5-methyl-2-(4-pyridin-2-yl-phenyl)-thiazol-4-yl]-propoxy}-phenyl)-propionicacid

MS (ES): 473.2 (M⁺+1).

Example 201(R)-3-(2-Methyl-4-{2-[5-methyl-2-(4-pyridin-2-yl-phenyl)-oxazol-4-yl]-propoxy}-phenyl)-propionicacid

MS (ES): 457.3 (M⁺+1).

Example 202(S)-3-(2-Methyl-4-{2-[5-methyl-2-(4-pyridin-2-yl-phenyl)-oxazol-4-yl]-propoxy}-phenyl)-propionicacid

MS (ES): 457.3 (M⁺+1).

Example 203(R)-3-(2-Methyl-4-{2-[5-methyl-2-(4-pyrimidin-2-yl-phenyl)-oxazol-4-yl]-propoxy}-phenyl)-propionicacid

MS (ES): 458.3 (M⁺+1).

Example 204(S)-3-(2-Methyl-4-{2-[5-methyl-2-(4-pyrimidin-2-yl-phenyl)-oxazol-4-yl]-propoxy}-phenyl)-propionicacid

MS (ES): 458.3 (M⁺+1).

Example 205(R)-3-(2-Methyl-4-{2-[5-methyl-2-(4-pyrimidin-2-yl-phenyl)-oxazol-4-yl]-propoxy}-phenyl)-propionicacid

MS (ES): 474.3 (M⁺+1).

Example 206(S)-3-(2-Methyl-4-{2-[5-methyl-2-(4-pyrimidin-2-yl-phenyl)-thiazol-4-yl]-propoxy}-phenyl)-propionicacid

MS (ES): 474.3 (M⁺+1).

Biological Assays

Binding and Cotransfection Studies

The in vitro potency of compounds in modulating PPAR receptors aredetermined by the procedures detailed below. DNA-dependent binding (ABCDbinding) is carried out using SPA technology with PPAR receptors.Tritium-labeled PPAR selective agonists are used as radioligands forgenerating displacement curves and IC₅₀ values with compounds of theinvention. Cotransfection assays are carried out in CV-1 cells. Thereporter plasmid contained an acylCoA oxidase (AOX) PPRE and TK promoterupstream of the luciferase reporter cDNA. Appropriate PPARs areconstitutively expressed using plasmids containing the CMV promoter. ForPPARα, interference by endogenous PPARγ in CV-1 cells is an issue. Inorder to eliminate such interference, a GAL4 chimeric system is used inwhich the DNA binding domain of the transfected PPAR is replaced by thatof GAL4, and the GAL4 response element is utilized in place of the AOXPPRE. Cotransfection efficacy is determined relative to PPARα agonistreference molecules. Efficacies are determined by computer fit to aconcentration-response curve, or in some cases at a single highconcentration of agonist (10 μM). These studies are carried out toevaluate the ability of compounds of the invention to bind to and/oractivate various nuclear transcription factors, particularly huPPARα(“hu” indicates “human”). These studies provide in vitro data concerningefficacy and selectivity of compounds of the invention. Furthermore,binding and cotransfection data for compounds of the invention arecompared with corresponding data for marketed compounds that act onhuPPARα.

The binding and cotransfection efficacy values found, for compounds ofthe invention and compounds of this invention which are useful formodulating a PPAR alpha receptor, are ≦100 nM and ≧50%, respectively.

Binding Assay:

DNA-dependent binding is carried out using Scintillation Proximity Assay(SPA) technology (Amersham Pharmacia Biotech). PPAR•, PPAR• and PPAR•receptors as well as their heterodimer partner RXR••receptor areprepared using a baculovirus expression system. Biotinylatedoligonucleotide ^(5′)TAATGTAGGTAATAGTTCAATAGGTCAAAGGG^(3′) is used forbinding of receptor dimers to Yttrium silicate streptavidin-coated SPAbeads. PPAR• labeled ligand is ³H-reference, and PPAR• and PPAR••labeledligands is ³H-reference with specific activity of 52 Ci/mmol and 90Ci/mmol, respectively. Competition binding reactions are carried out in10 mM HEPES pH 7.8, 80 mM KCl, 0.5 mM MgCl₂, 1 mM DTT, 0.5% CHAPS, 14%glycerol, using 2.5 •g of each of PPAR•, • or • and RXR• receptors, 5 nMto 10 •M of competing compounds and 30,000 cpm of corresponding labeledligand.

Co-Transfection Assay:

Co-transfection assays are performed in CV-1 cells using calciumphosphate coprecipitation as previously described (Berger et al. SteroidBiochem. Mol. Biol. 41:733, 1992; Mukherjee et al. Nature 386:407–410,1997). The reporter plasmid contained an acylCoA oxidase (AOX) PPRE andTK promoter upstream of the luciferase reporter cDNA. PPARs and RXR• areconstitutively expressed using plasmids containing the CMV promoter. ForPPAR••or••, interference by endogenous PPARs in CV-1 cells is eliminatedby using a GAL4 chimeric system in which the DNA binding domain of thetransfected PPAR••or•••is replaced by that of GAL4, and the GAL4response element is utilized in place of the AOX PPRE. CV-1 cells aretransfected in T225 cm² flasks in DMEM with 10% Fetal Bovine Serum(FBS). After an overnight incubation, transfected cells are trypsinizedand plated in 96 well dishes in DMEM media containing 10%charcoal-stripped FBS. After a 6 h incubation, cells are exposed to 0.1nM to 10•M of test compounds. Co-transfection efficacy is determinedusing reference compounds. Compounds of this invention that areselective for the PPAR• are at least 10-fold selective for PPAR•• overPPARα and PPARγ.

Evaluation of Triglyceride Reduction and HDL Cholesterol Elevation inHuapoAI Transgenic Mice

Seventeen different series of studies are performed to evaluate theeffect of compounds of the present invention upon HDL and triglyceridelevels in human apoAI mice. For each compound tested, seven to eightweek old male mice, transgenic for human apoAI (C57BL/6-tgn(apoa1)1rub,Jackson Laboratory, Bar Harbor, Me.) are acclimated in individual cagesfor two weeks with standard chow diet (Purina 5001) and water providedad libitum. After the acclimation, mice and chow are weighed andassigned to test groups (n=5) with randomization by body weight. Miceare dosed daily by oral gavage for 8 days using a 29 gauge, 1½ inchcurved feeding needle (Popper & Sons). The vehicle for the controls,test compounds and the positive control (fenofibrate 100 mg/kg) is 1%carboxymethylcellulose (w/v) with 0.25% tween 80 (w/v). All mice aredosed daily between 6 and 8 a.m. with a dosing volume of 0.2 ml. Priorto termination, animals and diets are weighed and body weight change andfood consumption are calculated. Three hours after last dose, mice areeuthanized with CO₂ and blood is removed (0.5–1.0 ml) by cardiacpuncture. After sacrifice, the liver, heart, and epididymal fat pad areexcised and weighed. Blood is permitted to clot and serum is separatedfrom the blood by centrifugation.

Cholesterol and triglycerides are measured colorimetrically usingcommercially prepared reagents (for example, as available from Sigma#339–1000 and Roche-#450061 for triglycerides and cholesterol,respectively). The procedures are modified from published work (McGowanM. W. et al., Clin Chem 29:538–542,1983; Allain C. C. et al., Clin Chem20:470–475,1974. Commercially available standards for triglycerides andtotal cholesterol, respectively, commercial quality control plasma, andsamples are measured in duplicate using 200 μl of reagent. An additionalaliquot of sample, added to a well containing 200 μl water, provided ablank for each specimen. Plates are incubated at room temperature on aplate shaker and absorbance is read at 500 nm and 540 nm for totalcholesterol and triglycerides, respectively. Values for the positivecontrol are always within the expected range and the coefficient ofvariation for samples is below 10%. All samples from an experiment areassayed at the same time to minimize inter-assay variability.

Serum lipoproteins are separated and cholesterol quantitated by fastprotein liquid chromatography (PPLC) coupled to an in line detectionsystem. Samples are applied to a Superose 6 HR size exclusion column(Amersham Pharmacia Biotech) and eluted with phosphate bufferedsaline-EDTA at 0.5 ml/min. Cholesterol reagent (for example, RocheDiagnostics Chol/HP 704036) at 0.16 ml/min mixed with the columneffluent through a T-connection and the mixture passed through a 15m×0.5 mm id knitted tubing reactor immersed in a 37 C water bath. Thecolored product produced in the presence of cholesterol is monitored inthe flow strem at 505 nm and the analog voltage from the monitor isconverted to a digital signal for collection and analysis. The change involtage corresponding to change in cholesterol concentration is plottedvs time and the area under the curve corresponding to the elution ofvery low density lipoprotein (VLDL), low density lipoprotein (LDL) andhigh density lipoprotein (HDL) is calculated using Perkin ElmerTurbochrome software.

Triglyceride Serum Levels in Mice Dosed with a Compound of the Inventionis compared to Mice Receiving the Vehicle to identify compounds thatcould be particularly useful for lowering triglycerides. Generally,triglyceride decreases of greater than or equal to 30% (thirty percent)compared to control following a 30 mg/kg dose suggests a compound thatcan be especially useful for lowering triglyceride levels.

The percent increase of HDLc serum levels in mice receiving a compoundof the invention is compared to mice receiving vehicle to identifycompounds of the invention that could be particularly useful forelevating HDL levels. Generally, and increase of greater than or equalto 25% (twenty five percent) increase in HDLc level following a 30 mg/kgdose suggests a compound that can be especially useful for elevatingHDLc levels.

It may be particularly desirable to select compounds of this inventionthat both lower triglyceride levels and increase HDLc levels. However,compounds that either lower triglyceride levels or increase HDLc levelsmay be desirable as well.

Evaluation of Glucose Levels in db/db Mice

The effects, upon plasma glucose of administering various dose levels offive different compounds of the present invention and the PPAR gammaagonist rosiglitazone or the PPAR alpha agonist fenofibrate, and thecontrol, to male db/db mice, are studied.

Five week old male diabetic (db/db) mice [for example,C57BlKs/j-m+/+Lepr(db), Jackson Laboratory, Bar Harbor, Me.] or leanlittermates are housed 6 per cage with food and water available at alltimes. After an acclimation period of 2 weeks, animals are individuallyidentified by ear notches, weighed, and bled via the tail vein fordetermination of initial glucose levels. Blood is collected (100 μl)from unfasted animals by wrapping each mouse in a towel, cutting the tipof the tail with a scalpel, and milking blood from the tail into aheparinized capillary tube. Sample is discharged into a heparinizedmicrotainer with gel separator and retained on ice. Plasma is obtainedafter centrifugation at 4° C. and glucose measured immediately.Remaining plasma is frozen until the completion of the experiment, whenglucose and triglycerides are assayed in all samples. Animals aregrouped based on initial glucose levels and body weights. Beginning thefollowing morning, mice are dosed daily by oral gavage for 7 days.Treatments are test compounds (30 mg/kg), a positive control agent (30mg/kg) or vehicle [1% carboxymethylcellulose (w/v)/0.25% Tween80 (w/v);0.3 ml/mouse]. On day 0.7, mice are weighed and bled (tail vein) 3 hoursafter dosing. Twenty-four hours after the 7^(th) dose (i.e., day 8),animals are bled again (tail vein). Samples obtained from consciousanimals on days 0, 7 and 8 are assayed for glucose. After the 24 hourbleed, animals are weighed and dosed for the final time. Three hoursafter dosing on day 8, animals are anesthetized by inhalation ofisoflurane and blood obtained via cardiac puncture (0.5–0.7 ml). Wholeblood is transferred to serum separator tubes, chilled on ice andpermitted to clot. Serum is obtained after centrifugation at 4° C. andfrozen until analysis for compound levels. After sacrifice by cervicaldislocation, the liver, heart and epididymal fat pads are excised andweighed.

Glucose is measured colorimetrically using commercially purchasedreagents. According to the manufacturers, the procedures are modifiedfrom published work (McGowan, M. W., Artiss, J. D., Strandbergh, D. R. &Zak, B. Clin Chem, 20:470-5 (1974) and Keston, A. Specific colorimetricenzymatic analytical reagents for glucose. Abstract of papers 129thMeeting ACS, 31C (1956).); and depend on the release of a mole ofhydrogen peroxide for each mole of analyte, coupled with a colorreaction first described by Trinder (Trinder, P. Determination ofglucose in blood using glucose oxidase with an alternative oxygenacceptor. Ann Clin Biochem, 6:24 (1969)). The absorbance of the dyeproduced is linearly related to the analyte in the sample. The assaysare further modified in our laboratory for use in a 96 well format. Thecommercially available standard for glucose, commercially availablequality control plasma, and samples (2 or 5 μl/well) are measured induplicate using 200 μl of reagent. An additional aliquot of sample,pipetted to a third well and diluted in 200 μl water, provided a blankfor each specimen. Plates are incubated at room temperature for 18minutes for glucose on a plate shaker (DPC Micormix 5) and absorbanceread at 500 nm on a plate reader. Sample absorbances are compared to astandard curve (100–800 for glucose). Values for the quality controlsample are always within the expected range and the coefficient ofvariation for samples is below 10%. All samples from an experiment areassayed at the same time to minimize inter-assay variability.

The results of the study, suggest compounds of the present inventionthat significantly reduced db/db mouse plasma glucose levels whileresulting in body weight gains that are generally less than thoseobserved for rosiglitazone.

Evaluation of the Effects of Compounds of the Present Invention UponA^(y) Mice Body Weight, Fat Mass, Glucose and Insulin Levels

Female A^(y) Mice

Female A^(y) mice are singly housed, maintained under standardizedconditions (22° C., 12 h light:dark cycle), and provided free access tofood and water throughout the duration of the study. At twenty weeks ofage the mice are randomly assigned to vehicle control and treated groupsbased on body weight and body fat content as assessed by DEXA scanning(N=6). Mice are then dosed via oral gavage with either vehicle or aCompound of this invention (50 mg/kg) one hour after the initiation ofthe light cycle (for example, about 7 A.M.) for 18 days. Body weightsare measured daily throughout the study. On day 14 mice are maintainedin individual metabolic chambers for indirect calorimetry assessment ofenergy expenditure and fuel utilization. On day 18 mice are againsubjected to DEXA scanning for post treatment measurement of bodycomposition.

The results of p.o. dosing of compound for 18 days on body weight, fatmass, and lean mass are evaluated and suggest which compounds of thisinvention can be especially useful for maintaining desirable weightand/or promoting desired lean to fat mass.

Indirect calorimetry measurements revealed a significant reduction inrespiratory quotient (RQ) in treated animals during the dark cycle[0.864±0.013 (Control) vs. 0.803±0.007 (Treated); p<0.001]. Thisreduction in RQ is indicative of an increased utilization of fat duringthe animals' active (dark) cycle. Additionally, treated animalsdisplayed significantly higher rates of energy expenditure than controlanimals (17.40±0.49 vs. 13.62±0.26 kcal/kg/hr, respectively).

Male KK/A^(y) Mice

Male KK/A^(y) mice are singly housed, maintained under standardizedconditions (22° C., 12 h light:dark cycle), and provided free access tofood and water throughout the duration of the study. At twenty-two weeksof age the mice are randomly assigned to vehicle control and treatedgroups based on plasma glucose levels. Mice are then dosed via oralgavage with either vehicle or a Compound of this invention (30 mg/kg)one hour after the initiation of the light cycle (7 A.M.) for 14 days.Plasma glucose, triglyceride, and insulin levels are assessed on day 14.

The results of p.o. dosing of compound for 14 days on plasma glucose,triglycerides, and insulin are evaluated to identify compounds of thisinvention that may be especially desired.

Method to Elucidate the LDL-cholesterol Total-cholesterol andTriglyceride Lowering Effect

Male Syrian hamsters (Harlan Sprague Dawley) weighing 80–120 g areplaced on a high-fat cholesterol-rich diet for two to three weeks priorto use. Feed and water are provided ad libitum throughout the course ofthe experiment. Under these conditions, hamsters becomehypercholesterolemic showing plasma cholesterol levels between 180–280mg/dl. (Hamsters fed with normal chow had a total plasma cholesterollevel between 100–150 mg/dl.) Hamsters with high plasma cholesterol (180mg/dl and above) are randomized into treatment groups based on theirtotal cholesterol level using the GroupOptimizeV211.xls program.

A Compound of this invention is dissolved in an aqueous vehicle(containing CMC with Tween 80) such that each hamster receives once aday approx. 1 ml of the solution by garvage at doses 3 and 30 mg/kg bodyweight. Fenofibrate (Sigma Chemical, prepared as a suspension in thesame vehicle) is given as a known alpha-agonist control at a dose of 200mg/kg, and the blank control is vehicle alone. Dosing is performed dailyin the early morning for 14 days.

Quantification of Plasma Lipids:

On the last day of the test, hamsters are bled (400 ul) from thesuborbital-sinus while under isoflurane anesthesia 2 h after dosing.Blood samples are collected into heparinized microfuge tubes chilled inice bath. Plasma samples are separated from the blood cells by briefcentrifugation. Total cholesterol and triglycerides are determined bymeans of enzymatic assays carried out automatically in the Monarchequipment (Instrumentation Laboratory) following the manufacturer'sprecedure. Plasma lipoproteins (VLDL, LDL and HDL) are resolved byinjecting 25 ul of the pooled plasma samples into an FPLC system elutedwith phosphate buffered saline at 0.5 ml/min through a Superose 6 HR10/30 column (Pharmacia) maintained room temp. Detection andcharacterization of the isolated plasma lipids are accomplished bypostcolumn incubation of the effluent with a Cholesterol/HP reagent (forexample, Roche Lab System; infused at 0.12 ml/min) in a knitted reactioncoil maintained at 37° C. The intensity of the color formed isproportional to the cholesterol concentration and is measuredphotometrically at 505 nm.

The effect of administration of a Compound of this invention for 14 daysis studied for the percent reduction in LDL level with reference to thevehicle group. The LDL-lowering efficacy for certain compounds of thisinvention is markedly more potent than that of fenofibrate. Compounds ofthis invention that decrease LDL greater than or equal to 30% (thirtypercent) compared to vehicle can be especially desired.

The total-cholesterol and triglyceride lowering effects of a Compound ofthis invention is also studied. The data for reduction in totalcholesterol and triglyceride levels after treatment with a compound ofthis invention for 14 days is compared to the vehicle to suggestcompounds that can be particularly desired.

Method to Elucidate the Fibrinogen-lowering Effect of PPAR•Modulators

Zucker Fatty Rat Model:

The life phase of the study on fibrinogen-lowering effect of compoundsof this invention is part of the life phase procedures for theantidiabetic studies of the same compounds. On the last (14^(th)) day ofthe treatment period, with the animals placed under surgical anesthesia,˜3 ml of blood is collected, by cardiac puncture, into a syringecontaining citrate buffer. The blood sample is chilled and centrifugedat 4° C. to isolate the plasma that is stored at −70° C. prior tofibrinogen assay.

Quantification of Rat Plasma Fibrinogen:

Rat plasma fibrinogen levels are quantified by using a commercial assaysystem consists of a coagulation instrument following the manufacturer'sprotocol. In essence, 100 ul of plasma is sampled from each specimen anda 1/20 dilution is prepared with buffer. The diluted plasma is incubatedat 37° C. for 240 seconds. Fifty microliters of clotting reagentthrombin solution (provided by the instrument's manufacturer in astandard concentration) is then added. The instrument monitores theclotting time, a function of fibrinogen concentration quantified withreference to standard samples.

RESULTS

Compounds of this invention are capable of lowering fibrinogen level invivo. Compounds that lower fibrinogen level greater than vehicle can beespecially desired.

Cholesterol and triglyceride lowering effects of compounds of thisinvention are also produced in Zucker rats.

Method to Elucidate the Anti-body Weight Gain and Anti-appetite Effectsof Compounds of this Invention

Fourteen-Day Study in Zucker Fatty Rat¹ or ZDF Rat² Models:

Male Zucker Fatty rats, non-diabetic (Charles River Laboratories,Wilmington, Mass.) or male ZDF rats (Genetic Models, Inc, Indianapolis,Ind.) of comparable age and weight are acclimated for 1 week prior totreatment. Rats are on normal chow and water is provided ad libitumthroughout the course of the experiment.

Test compounds are dissolved in an aqueous vehicle such that each ratreceives once a day approximately 1 ml of the solution by garvage atdoses 0.1, 0.3, 1 and 3 mg/kg body weight. Fenofibrate (Sigma Chemical,prepared as a suspension in the same vehicle) a known alpha-agonistgiven at doses of 300 mg/kg, as well as the vehicle are controls. Dosingis performed daily in the early morning for 14 days. Over the course ofthe experiment, body weight and food consumption are monitored.

Using this assay, compounds of this invention can result in significantweight reduction.

EQUIVALENTS

While this invention has been particularly shown and described withreferences to preferred embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details may bemade therein without departing from the scope of the inventionencompassed by the appended claims.

1. A compound of the formula Formula I:

and pharmaceutically acceptable salts thereof, wherein; (a) R3 isselected from the group consisting of hydrogen, (C₁–C₄)alkyl, halo, and(C₁–C₆)alkoxy; (b) R4 is methyl; (c) R30 and R40 are each hydrogen; (d)R5 is selected from the group consisting of (C₂–C₄)alkyl,(C₁–C₆)alkenyl, aryl(C₀–C₄)alkyl, aryloxy(C₀–C₄)alkyl,arylthio(C₀–C₄)alkyl, wherein said aryl(C₀–C₄)alkyl,aryloxy(C₀–C₄)alkyl, and arylthio(C₀–C₄)alkyl are each independentlyoptionally substituted with from one to three substituents eachindependently selected from R5′, and further wherein when R5 is alkyl,R5 can optionally combine with W to form a 6 membered cycloheteroalkylring that is fused with the oxazole or thiazole ring to which the R5group is attached; (e) R5′ are each independently selected from thegroup consisting of halo, —(O)—(C₁–C₅)alkylCOOH, C₁–C₅alkyl,C₁–C₅alkylCOOH, and CF₃; (f) R6 is selected from the group consisting oftrihalomethyl, trihalomethoxy, hydroxyl(C₀–C₃)alkyl, (C₁–C₄)alkyl,(C₁–C₆)alkyINC(O)—, tetramethyldioxaborolanyl, halo, —C(O)(C₁–C₄)alkyl,—O—(C₁–C₂)alkyl-CO₂H, aryloxy, arylthio, —C(O)N(C₁–C₆)alkyl,(C₁–C₄)alkoxy, tetrahydropyranyloxy, morpholinyl, (C₅–C₆)cycloalkyloxy,(C₅–C₆)heterocyclo-oxy, pyridinyl, pyrimidinyl, pyrazinyl andaryl(C₀–C₄)alkyl, wherein said pyridinyl, pyrimidinyl, pyrazinyl,aryl(C₀–C₄)alkyl, aryloxy, (C₅–C₆)heterocyclo-oxy, and arylthio are eachoptionally substituted with from one to three substituents independentlyselected from R6′; (g) R6′ and R9′ are each independently selected fromthe group consisting of CF₃, C₁–C₄alkyl, halo, hydroxy(C₁–C₃)alkyl,C₁–C₃alkoxy, and —C(O)CH₃; (h) R7 and R8 are each independently selectedfrom the group consisting of hydrogen, CF₃, and (C₁–C₃)alkyl; (i) R9 isselected from the group consisting of C₁–C₅alkyl, C₁–C₅alkenyl, andarylC₀–C₃alkyl, wherein said arylalkyl is optionally substituted withfrom one to three substituents each independently selected from R9′; (j)R10 is selected from the group consisting of hydrogen, and C₁–C₅alkyl;(k) Q is selected from the group consisting of O, a single bond, andCH₂; (l) T₁ is C; (m) W is selected from the group consisting of CH₂,C(O)N(R21), N(R21), N(R21)CH₂, O, OCH₂, S, and SO₂; (n) R21 is selectedfrom the group consisting of hydrogen and C₁–C₂alkyl; (o) X is selectedfrom the group consisting of C, CH₂C, and CCH₂; (p) Y and Z are eachindependently selected from the group consisting of O, N and S, whereinat least one of Y and Z is selected from the group consisting of O andS; (q) A is an functional group selected from the group consisting ofcarboxyl, C₁–C₃alkylnitrile, carboxamide, and (CH₂)_(n) COOR19; (r) n is0, 1, 2 or 3; (s) R19 is selected from the group consisting of hydrogen,and C₁–C₃alkyl; and (t) Further provided that when O is O and R5 ismethyl, then R9 is benzyl.
 2. A compound as claimed by claim 1 wherein Wis O.
 3. A compound as claimed by claim 1 wherein W is S.
 4. A compoundas claimed by claim 3 wherein Q is O.
 5. A compound as claimed by claim3 wherein Q is C.
 6. A compound as claimed by claim 4 or 5 wherein Qbonded to the phenyl ring in a meta orientation with respect to W.
 7. Acompound as claimed by claim 4 or 5 wherein R3 is methyl.
 8. A compoundas claimed by claim 4 or 5 wherein X is C.
 9. A compound as claimed byclaim 2 wherein X is CH₂C.
 10. A compound as claimed by claim 4 or 5wherein R9 is C₁–C₃alkyl.
 11. A compound as claimed by claim 2 whereinR9 is benzyl.
 12. A compound as claimed by claim 8 or 9 wherein Y is N.13. A compound as claimed by claim 8 or 9 wherein Z is O.
 14. A compoundas claimed by claim 8 or 9 wherein Z is S.
 15. A compound as claimed byclaim 12 wherein R5 is C₂–C₄alkyl.
 16. A compound as claimed by claims 8or 9 wherein R6 is selected from the group consisting of trihalomethoxy,(C₁–C₆)alkylNC(O)—, tetramethyldioxaborolanyl, —C(O)(C₁–C₄)alkyl,—O—(C₁–C₂)alkyl-CO₂H, aryloxy, arylthio, —C(O)N(C₁–C₆)alkyl,morpholinyl, and (C₅–C₆)cycloalkyloxy.
 17. A compound as claimed byclaim 12 wherein R6 is CF₃.
 18. A compound as claimed by claim 12wherein A is COOH.
 19. A compound as claimed by claim 1 wherein thecompound is selected from the group consisting of(4-{1-[4-[2-(2-Chloro-6-fluoro-phenyl)-ethyl]-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethylsulfanyl}-2-methyl-phenoxy)-aceticacid,(4-{1-[4-[2-(2-Chloro-6-fluoro-phenyl)-ethyl]-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-2-methyl-phenoxy)-acetic,3-(4-{1-[4-[2-(2-Chloro-6-fluoro-phenyl)-ethyl]-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionicacid,(2-Methyl-4-{1-[4-phenethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethylsulfanyl}-phenoxy)-aceticacid,(2-Methyl-4-{1-[4-phenethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-phenoxy)-aceticacid,3-(2-Methyl-4-{1-[4-phenethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-phenyl)-propionicacid,(2-Methyl-4-{1-[4-phenyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethylsulfanyl}-phenoxy)-aceticacid,3-(2-Methyl-4-{1-[4-phenyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-phenyl)-propionicacid,(4-{1-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethylsulfanyl}-2-methyl-phenoxy)-aceticacid,(4-{1-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-2-methyl-phenoxy)-aceticacid,3-(4-{1-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionicacid,3-(4-{1-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethylsulfanyl}-2-methyl-phenyl)-propionicacid,(2-Methyl-4-{1-[4-phenylsulfanylmethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethylsulfanyl}-phenoxy)-aceticacid,(4-{1-[4-(3,5-Bis-trifluoromethyl-phenoxymethyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethylsulfanyl}-2-methyl-phenoxy)-aceticacid,(4-{1-[4-(2-Chloro-6-fluoro-phenoxymethyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethylsulfanyl}-2-methyl-phenoxy)-aceticacid,3-(4-{1-[4-(3,5-Bis-trifluoromethyl-phenoxymethyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionicacid,3-(4-{1-[4-(2-Chloro-6-fluoro-phenoxymethyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionicacid,(4-{1R-[4-[2-(2-Chloro-6-fluoro-phenyl)-ethyl]-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethylsulfanyl}-2-methyl-phenoxy)-aceticacid,(4-{1S-[4-[2-(2-Chloro-6-fluoro-phenyl)-ethyl]-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethylsulfanyl}-2-methyl-phenoxy)-aceticacid,(2-Methyl-4-{1S-[4-phenethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-phenoxy)-aceticacid, (2-Methyl-4-{1R-[4-phenethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-phenoxy)-aceticacid,(2-Methyl-4-{1R-[4-phenethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethylsulfanyl}-phenoxy)-aceticacid,(R)-(4-{1-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethylsulfanyl}-2-methyl-phenoxy)-aceticacid,(S)-4-{1-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethylsulfanyl}-2-methyl-phenoxy)-aceticacid,(S)-(4-{1-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-2-methyl-phenoxy)-aceticacid,(R)-4-{1-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-2-methyl-phenoxy)-aceticacid,(S)-3-(4-{1-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionicacid,(R)-3-(4-{1-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionicacid,(R)-3-(4-{1-[4-(2-Chloro-6-fluoro-phenoxymethyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionicacid, (S)-3-(4-{1-[4-(2-Chloro-6-fluoro-phenoxymethyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-2-methyl-phenyl-propionicacid,(R)-4-{1-[4-(2-Chloro-6-fluoro-phenoxymethyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethylsulfanyl}-2-methyl-phenoxy)-aceticacid,(S)-(4-{1-[4-(2-Chloro-6-fluoro-phenoxymethyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethylsulfanyl}-2-methyl-phenoxy)-aceticacid,(S)-(2-Methyl-4-{1-[4-phenylsulfanylmethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethylsulfanyl}-phenoxy)-aceticacid,(R)-2-Methyl-4-{1-[4-phenylsulfanylmethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-4ethylsulfanyl}-phenoxy)-aceticacid,(S)-3-(2-Methyl-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-phenyl)-propionicacid,3-(4-{1-[4-Ethyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionicacid,(4-{1-[4-Ethyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethoxy}-2-methyl-phenoxy)-aceticacid,(4-{1-[4-Ethyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethylsulfanyl}-2-methyl-phenoxy)-aceticacid,(4-{1R-[4-Ethyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethylsulfanyl}-2-methyl-phenoxy)-aceticacid,(4-{1S-[4-Ethyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethylsulfanyl}-2-methyl-phenoxy)-aceticacid,3-(4-{1-[4-tert-Butyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionicacid,3-(4-{1-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionicacid,3-(4-{2-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-propoxy}-2-methyl-phenyl)-propionicacid, 3-[4-(1-{4-Isopropyl-2-[4-(4,4,5,-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-oxazol-5-yl}-ethoxy)-2-methyl-phenyl]-propionicacid methyl ester,3-(4-{1-[2-(4-Hydroxy-phenyl)-4-isopropyl-oxazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionicacid methyl ester,3-(4-{1-[4-Isopropyl-2-(4-methoxy-phenyl)-oxazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionicacid,3-(4-{1-[2-(3-Cyclopentyloxy-phenyl)-4-isopropyl-oxazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionicacid,3-[4-(1-{4-Isopropyl-2-[3-(tetrahydro-pyran-4-yloxy)-phenyl]-oxazol-5-yl}-ethoxy)-2-methyl-phenyl]-propionicacid,3-(4-{1-[2-(4-Cyclopentyloxy-phenyl)-4-isopropyl-oxazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionicacid,3-(4-{1-[4-Isopropyl-2-(4-piperidin-1-yl-phenyl)-oxazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionicacid,3-(4-{1-[4-Isopropyl-2-(3-piperidin-1-yl-phenyl)-oxazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionicacid,3-(4-{1-[4-Isopropyl-2-(3-morpholin-4-yl-phenyl)-oxazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionicacid,3-(4-{1-[4-Isopropyl-2-(4-morpholin-4-yl-phenyl)-oxazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionicacid, and3-(4-{1-[2-(4-Hexylcarbamoyl-phenyl)-4-isopropyl-oxazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionicacid.
 20. A compound as claimed by claim 1 wherein the compound is the Sconformation.
 21. A compound as claimed by claim 1 wherein the compoundis the R conformation.
 22. A pharmaceutical composition, comprising apharmaceutically acceptable carrier and at least one compound as claimedby claim
 1. 23. A method of treating diabetes mellitus in a mammal,comprising the step of administering to the mammal in need thereof, atherapeutically effective amount of at least one compound of claim 1.24. A method of creating Syndrome X in a mammal, comprising the step ofadministering to the mammal in need thereof, a therapeutically effectiveamount of at least one compound of claim
 1. 25. A method of treatingatherosclerosis in a mammal, comprising the step of administering to themammal in need thereof, a therapeutically effective amount of at leastone compound of claim 1.